Devices, Systems and Methods for Treating Urological and Gastrointestinal Disorders by Electrical Stimulation of the Foot

ABSTRACT

Provided herein are devices, systems, and methods for treating urological and gastrointestinal disorders, including bedwetting, through stimulation of the dorsal or plantar surface of the foot, including the superficial peroneal nerve and branches thereof, such as the dorsal intermediate and medial cutaneous nerves, or the medial and/or and lateral plantar nerves. The device facilitates placement of electrodes on the foot. Also provided herein is a system including the device, a pulse generator, and a controller, and methods of manufacturing and using the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Nos. 62/096,226, filed Dec. 23, 2014, 62/096,265, filed Dec.23, 2014, and 62/235,849, filed Oct. 1, 2015, each of which isincorporated herein by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under Grant Nos.DK-068566, DK-090006, and DK-094905 awarded by the National Institutesof Health. The government has certain rights in the invention.

BACKGROUND

Overactive bladder (OAB) is a syndrome characterized by urinary urgencywith or without urge incontinence, often with frequency and nocturia.OAB patients have a significantly impaired quality of life. First linetherapy involves such behavioral therapies as fluid management, pelvicfloor muscle physical therapy, and bladder training. Pharmacotherapy isoffered concomitantly or subsequently if behavioral strategies fail.Anti-muscarinics are the most common drugs used for OAB treatment.However, drug therapy often has low efficacy and significant adverseeffects. Consequently, 70% of patients discontinue therapy within thefirst year of treatment.

FDA-approved treatments for patients that have failed behavioral andanti-muscarinic therapies include intradetrusor injection ofonabotulinumtoxinA, sacral neuromodulation, or tibial neuromodulation.OnabotulinumtoxinA requires repeat injections every 6-12 months andresults in adverse events such as urinary tract infection and urinaryretention. Sacral neuromodulation is invasive, requiring surgery toimplant both the electrodes and the neurostimulator. Furthermore, thecosts associated with sacral neuromodulation have limited this optionfor some OAB patients. Tibial neuromodulation is a minimally invasive,office-based procedure that involves inserting a needle electrode nearthe ankle to stimulate the tibial nerve. The tibial nerve is stimulatedfor 30 minutes each week for 12 consecutive weeks, followed by onestimulation per month to maintain efficacy.

Additionally, nocturnal enuresis, or bedwetting at night, is a verycommon problem of childhood. The American Psychiatric Associationdefines nocturnal enuresis as wetting two or more times per week for atleast three consecutive months in children over the age of five. About80% of the bedwetting children have never achieved nighttime dryness fora period more than 6 months. The other 20% children have bedwettingre-appear after achieving more than 6 months of nighttime dryness. Mostbedwetting children (80%) are healthy without known lower urinary tractdiseases. The pathology and etiology underlying bedwetting is not fullyunderstood. Current treatment options for effectively and safely curingbedwetting are cumbersome and most are not readily effective.

Behavioral therapy and bedwetting alarms are the first-line treatmentsfor bedwetting. Although behavioral therapy can reduce the frequency ofbedwetting, its efficacy is very limited. Further, while alarm trainingis an effective treatment, it can produce a significant amount of stressto the child and family due to disruptions of nighttime sleep,especially to a family with crowded housing or intolerance to sleepdisturbance. Other problems in using a bedwetting alarm include thedifficulties in setting up each night, failure of the alarm to wake thechild, false alarm, alarm failure, and skin irritation. Due to theseproblems, many children and families either decline or discontinue theuse of bedwetting alarms.

Medications are used to treat the symptoms of bedwetting afterbehavioral and alarm therapies do not produce beneficial effects, butmedications, such as imipramine and desmopressin, do not curebedwetting. At present, a safe, effective, and easy-to-use treatment forbedwetting in children is not available.

Several non-invasive neuromodulation approaches have been investigatedpreviously in an attempt to treat bladder overactivity (but heretoforehave not been tested for bed wetting), including intra-vaginalsimulation. However, these approaches targeted very inconvenientlocations causing discomfort and difficulty in maintaining theelectrodes in place for an extended time period. Accordingly, a needexists in the art for a device, system, and method of using the same fornon-invasive, non-painful stimulation of nerves that can modulateurological and gastrointestinal activity and treat urological (includingbed wetting) and gastrointestinal disorders in humans.

SUMMARY

The devices, systems, and methods described herein are useful forstimulating a physiological response and for inhibiting or treatingconditions, such as overactive bladder (OAB) symptoms including bladderoveractivity, urinary frequency, urinary urgency, urinary incontinence(including without limitation bedwetting, a type of urinaryincontinence), interstitial cystitis (IC), urinary retention, and pelvicpain; and gastrointestinal conditions, such as fecal incontinence,irritable bowel syndrome (IBS), and constipation.

The present devices, systems, and methods are superior to prior methodsbecause they do not involve invasive activities, such as electrodeimplantation, for instance, as is currently used for urinaryincontinence, and do not require precise placement of the electrodes.The devices, systems, and methods disclosed herein involve electricalstimulation applied to the skin of the dorsal or plantar surface of thefoot of a patient, unexpectedly being able to inhibit bladdercontractions in a non-invasive manner that is easily implemented bypatients and which is amenable to comfortable placement and stimulationby electrodes in foot orthotics, thin films (rigid or flexible) andother devices that can comfortably fit on the patient's foot, greatlyenhancing patient independence and reducing costs of such procedures.The following are exemplary aspects, illustrative of the devices,systems and methods described herein. It should be noted that thedevices, systems, and methods described herein apply equally to the leftand right foot, and the methods may stimulate the right foot, the leftfoot, alternate stimulation, and/or stimulate both feet at the sametime.

Provided herein is an electrode-containing device. In one aspect, thedevice includes a base adapted to cover a portion of a plantar surfaceof a human foot including a portion of the forefoot overlaying aplurality of branches of the medial or lateral plantar nerves and aportion of the hindfoot overlaying the medial and lateral plantarnerves; a first electrode attached to the base at a position adapted tothe hindfoot to contact skin overlaying the medial and lateral plantarnerves; a second electrode attached to the base at a position adapted tothe forefoot to contact skin overlaying a plurality of branches of themedial or lateral plantar nerves in the forefoot; and a first and secondelectrical lead attached to the first and second electrodes,respectively.

In another aspect, the device includes a base adapted to cover a portionof a dorsal surface of a human foot including a portion of the forefootoverlaying a plurality of branches of the dorsal intermediate and medialcutaneous nerves, deep peroneal nerve, sural nerve, and/or saphenousnerve, and a portion of the hindfoot overlaying the superficial peronealnerve, deep peroneal nerve, and/or saphenous nerve; a first electrodeattached to the base at a position adapted to a dorsal portion of thehindfoot to contact skin overlaying the superficial peroneal nerve, deepperoneal nerve, and/or saphenous nerve; a second electrode attached tothe base at a position adapted to a dorsal portion of the forefoot tocontact skin overlaying a plurality of branches of the dorsalintermediate and medial cutaneous nerves, deep peroneal nerve, suralnerve, and/or saphenous nerve in the forefoot; and a first and secondelectrical lead attached to the first and second electrodes,respectively.

In aspects, the first electrode of the device is a cathode and thesecond electrode is an anode. In some aspects, the first electrode is ananode and the second electrode is a cathode.

In aspects, the first electrode or the second electrode overlays atleast 50% of the width of the sole at the forefoot.

In aspects, the first electrode overlays at least a portion of themetatarsophalangeal joint. In some aspects, the second electrodeoverlays at least a portion of the metatarsophalangeal joint.

In aspects, the first electrode overlays at least a portion of thecalcaneus bone. In some aspects, the second electrode overlays at leasta portion of the calcaneus bone.

In aspects, the first electrode overlays a predominance of branches ofthe medial and lateral plantar nerves in the forefoot. In some aspects,the second electrode overlays a predominance of branches of the medialand lateral plantar nerves in the forefoot.

In aspects, the base of the device has a perimeter having the shape of asole of a foot, and optionally is an orthotic insert. In some aspects,the base has a perimeter having the shape of the dorsal area of a footfrom the proximal phalanges to the talocrural joint.

In aspects, the base of the device is a thin polymeric film having anadhesive on a side comprising the electrodes and facing the foot.

In aspects, the device further includes one or more connectors for anexternal pulse generator attached to the leads.

In aspects, the device further includes an adhesive on a surface of thebase and/or electrodes for removably securing the device to a patient'sfoot.

In aspects, the base of the device is shaped substantially like aplantar surface or sole of a human foot. In some aspects, the base isshaped substantially to interact with the dorsal surface of a humanfoot.

Also provided herein is an electrical nerve stimulation system. Inaspects, the system includes a device as described herein and a pulsegenerator external to the electrode-containing device and connected tothe leads, configured to generate pulses of pulsewidth 0.01-3 ms between1-100 V and 1-100 mA, at frequency 1-50 Hz.

In aspects, the system includes an adjustment mechanism for adjustingone or more parameters of the pulses. In aspects, the adjustmentmechanism includes a wireless receiver in wireless communication with awireless controller.

In aspects, the pulse generator of the system produces monophasic,rectangular pulses or biphasic pulses. In some aspects, the pulsegenerator provides pulses having a pulse width of 0.2 ms at 5 Hz, andwherein the intensity of the pulses is from 2-6 times a toe twitchthreshold of a patient. In some aspects, the pulse generator provides afixed output of pulses of pulsewidth 0.01-3 ms between 1-100 V and 1-100mA, at frequency 1-50 Hz.

Also provided herein is a method of treating urological orgastrointestinal disorders. In aspects, the method includes the steps ofapplying an electrode-containing device as described herein to a foot ofa patient in need of such treatment, wherein the electrode-containingdevice is attached to a pulse generator external to theelectrode-containing device comprising a connector for connecting thepulse generator to the device; and stimulating the patient's foot withthe device with pulses of pulsewidth 0.01-3 ms between 1-100 V and 1-100mA, at frequency 1-50 Hz, thereby stimulating either the lateral and/ormedial plantar nerves or the dorsal intermediate and medial cutaneousnerves, deep peroneal nerve, sural nerve, and/or saphenous nerves of thepatient.

In aspects, the urological or gastrointestinal disorder is one or moreof: overactive bladder (OAB) symptoms including bladder overactivity,urinary frequency, urinary urgency, urinary incontinence; interstitialcystitis (IC); urinary retention; pelvic pain; fecal incontinence;irritable bowel syndrome (IBS); and constipation. In some aspects theurological or gastrointestinal disorder is urinary incontinence.

In some aspects, the urinary incontinence is bedwetting and the devicedelivers pulses of a frequency of 5 Hz, 0.2 ms pulsewidth, and/or fromgreater than 0 mA to 100 mA, preferably from 2-6 times a toe twitchthreshold of a patient.

In aspects of the method, the patient's foot is stimulated for from 1 to360 minutes. In some aspects, the patient's foot is stimulated for atleast 30 minutes. In some aspects, the patient's foot is stimulated forat least 180 minutes.

In aspects, the method further includes the step of administering ananti-muscarinic compound to the patient. In some aspects, theanti-muscarinic compound is one or more of atropine, benztropine,biperiden, ipratropium, oxitropium, tiotropium, glycopyrrolate,oxybutynin, tolterodine, chlorpheniramine, diphenhydramine,dimenhydrinate, orphenadrine, trihexyphenidyl, and dicyclomine. In someaspects, the anti-muscarinic compound is tolterodine.

In aspects of the method, the anti-muscarinic compound is administeredat between 0.003 and 1 mg/kg and is administered orally or parenterally.

In aspects, the method further includes the step of administering to apatient in need thereof a serotonin reuptake inhibitor and/or aserotonin receptor antagonist. In some aspects, the serotonin reuptakeinhibitor is one or more of alaproclate, citalopram, dapoxetine,escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine,omiloxetine, panuramine, paroxetine, pirandamine, duloxetine,dapoxetine, sertraline, and zimelidine and the serotonin receptorantagonist is one or more of alprenolol, AV-965, BMY-7,378,cyanopindolol, dotarizine, flopropione, GR-46,611, isodocyanopindolol,isamoltane, lecozotan, methiothepin, methysergide, MPPF, NAN-190,oxprenolol, pindobind, pindolol, propranolol, risperidone, robalzotan,SB-649,915 (which acts as both a reuptake inhibitor and a receptorantagonist), SDZ-216,525, spiperone, spiramide, spiroxatrine, UH-301,WAY-100135, WAY 100635, and xylamidine.

In some aspects of the method, the serotonin reuptake inhibitor isduloxetine. In some aspects, the serotonin receptor antagonist isWAY100635.

In aspects, the method further includes the step of administering both aserotonin reuptake inhibitor and a serotonin receptor antagonist. Insome aspects, the serotonin reuptake inhibitor is duloxetine and theserotonin receptor antagonist is WAY100635 and duloxetine isadministered at between 0.003 and 5 mg/kg and WAY100635 is administeredat between 0.1 and 1 mg/kg. In some aspects, the serotonin reuptakeinhibitor or the serotonin receptor antagonist are administered orallyor parenterally.

In aspects, the method further includes the step of administering anopioid drug to the patient. In some aspects, the opioid drug is one ormore of tramadol, morphine, codeine, thebaine, diacetylmorphine(morphine diacetate; heroin), nicomorphine (morphine dinicotinate),dipropanoylmorphine (morphine dipropionate), desomorphine,acetylpropionylmorphine, dibenzoylmorphine, diacetyldihydromorphine,hydromorphone, hydrocodone, oxycodone, oxymorphone, ethylmorphine,buprenorphine, fentanyl, pethidine, levorphanol, methadone,dextropropoxyphene, tapentadol, endorphins, enkephalins, dynorphins, andendomorphins. In some aspects the opioid drug is tramadol.

In aspects of the method, the opioid drug is administered at between0.003 and 1 mg/kg, and is administered orally or parenterally.

Also provided herein is a method of manufacturing anelectrode-containing device. In aspects the method includes the steps offorming a base adapted to cover a portion of a bottom surface of a humanfoot including a portion of the forefoot overlaying a plurality ofbranches of the medial or lateral plantar nerves and a portion of thehindfoot overlaying the medial and lateral plantar nerves; attaching afirst electrode to the base at a position in the base adapted to contactskin overlaying the medial and lateral plantar nerves; attaching asecond electrode to the base at a position in the base adapted tocontact skin overlaying a plurality of branches of the medial or lateralplantar nerves in the forefoot; and attaching electrode leads for thefirst and second electrodes to the base.

In some aspects the method includes the steps of forming a base adaptedto cover a portion of a dorsal surface of a human foot including aportion of the forefoot overlaying a plurality of branches of the dorsalintermediate and medial cutaneous nerves, deep peroneal nerve, suralnerve, and/or saphenous nerve, and a portion of the hindfoot overlayingthe superficial peroneal nerve, deep peroneal nerve, and/or saphenousnerve; attaching a first electrode to the base at a position in the baseadapted to contact skin overlaying the superficial peroneal nerve, deepperoneal nerve, and/or saphenous nerve; attaching a second electrode tothe base at a position in the base adapted to contact skin overlaying aplurality of branches of the dorsal intermediate and medial cutaneousnerves, deep peroneal nerve, sural nerve, and/or saphenous nerve in theforefoot; and attaching electrode leads for the first and secondelectrodes to the base.

In aspects, the first electrode is adapted to engage skin of the sole ofthe foot over at least 50% of the width of the forefoot. In someaspects, the first electrode is adapted to engage skin of the dorsalsurface of the foot over at least 50% of the width of the forefoot.

In some aspects, the second electrode is adapted to engage skin of thesole of the foot over at least 50% of the width of the forefoot. Insonic aspects, the second electrode is adapted to engage skin of thedorsal surface of the foot over at least 50% of the width of theforefoot.

In aspects of the method, a plurality of the devices are manufactured toaccommodate a plurality of standardized foot sizes.

In aspects, the electrodes are embedded within the base.

In aspects, the base is configured to have a perimeter having the shapeof a sole of a foot, and optionally is an orthotic insert. In someaspects, the base is configured to have a perimeter having the shape ofthe dorsal area of a foot from the proximal phalanges to the talocruraljoint. In some aspects, electrode leads are embedded within the base.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of the dorsal (top) surface of a humanfoot, showing the bones of the human foot.

FIG. 2 is a schematic diagram of the plantar (bottom) surface of a humanfoot, showing the bones of the human foot.

FIG. 3 is a schematic diagram of the dorsal (top) surface of a humanfoot, showing the bones of the human foot and the nerves, including thesuperficial peroneal nerve, dorsal intermediate cutaneous nerve, dorsalmedial cutaneous nerve, deep peroneal nerve, sural nerve, and saphenousnerve.

FIG. 4 is a schematic diagram of the plantar (bottom) surface of a humanfoot, showing the bones of the human foot and the nerves, including thelateral and medial plantar nerves.

FIG. 5 is a schematic diagram of aspects of base shapes and electrodeplacement on the dorsal surface of a foot of a device described herein.

FIG. 6 is a schematic diagram of aspects of base shapes and electrodeplacement on the plantar surface of a foot of a device described herein.

FIG. 7 is a schematic diagram of the side of a human foot and one aspectof a device for placement on the dorsal surface of a foot as describedherein.

FIG. 8 is a schematic diagram of the side of a human foot and one aspectof a device for placement on the plantar surface of a foot as describedherein.

FIG. 9 is a schematic diagram of one aspect of a system including adevice for placement on a dorsal surface of the foot as describedherein.

FIG. 10 is a schematic diagram of one aspect of a system including adevice for placement on a dorsal surface of the foot as describedherein.

FIG. 11 is a schematic diagram of one aspect of a system including adevice for placement on a plantar surface of the foot as describedherein.

FIG. 12 is a schematic diagram of one aspect of a system including adevice for placement on a plantar surface of the foot as describedherein.

FIG. 13 is a schematic diagram of the (a) bottom and (b) side of a humanfoot and placement on the plantar surface of the foot of one aspect of adevice as described herein.

FIG. 14 is a block diagram of electronic design of a device as describedherein.

FIG. 15 shows the mean bladder volume per void measured during a 24-hourperiod before foot stimulation, after foot stimulation within a 5 hourperiod, and after foot stimulation during a 36 hour period.

FIG. 16 shows foot inhibition of bladder overactivity induced by 0.25%acetic acid (AA) irritation before duloxetine treatment: A.Cystometrogram (CMG) pressure traces during saline or AA infusion withand without foot stimulation. B. Summarized bladder capacity underdifferent CMG conditions (N=8 cats).

FIG. 17 shows CMG traces showing the dose-dependent effect of a range ofintravenous doses of duloxetine and foot inhibition on bladderoveractivity caused by AA irritation. A. Control CMGs without footstimulation. B. CMGs during 2 T stimulation. C. CMGs during 4 Tstimulation.

FIG. 18 shows summarized results of the dose-dependent effect ofduloxetine administered intravenously and foot inhibition on bladderoveractivity induced by AA irritation (N=8 cats).

FIG. 19 shows inhibition of bladder overactivity induced by combinationof duloxetine and WAY100635 treatment: A. CMG pressure traces duringacetic acid (AA) infusion after 3 mg/kg duloxetine and then after 0.5mg/kg WAY100635 intravenously. B. Summarized bladder capacities measuredbefore and after WAY100635 treatment (N=4 cats).

FIG. 20 shows foot inhibition of bladder overactivity caused by 0.25%AA: A. CMG pressure trace during saline or AA infusion at rate of 1ml/min with or without foot stimulation prior to tolterodineadministration. Stimulation denoted by solid black bar under thepressure trace. B. Summarized results (N=6 cats) showing average bladdercapacity normalized to saline control.

FIG. 21 shows dose-dependent effect of tolterodine and foot inhibitionon bladder overactivity caused by AA irritation. A. Control CMGs withoutfoot stimulation after increasing doses of tolterodine. B. CMGs during 2T foot stimulation. C. CMGs during 4 T foot stimulation.

FIG. 22 shows summarized results of dose dependent effect of tolterodineand foot inhibition. A. Bladder overactivity caused by AA irritation. B.Amplitude of micturition contraction.

FIG. 23 shows foot stimulation schedule and electrode location in anexperiment using a device as described herein.

FIG. 24A-24B shows results of daily voiding from diaries in subjectsundergoing foot stimulation as described herein. 24A (upper panel)Voiding frequency; 24A (lower panel) Urgency frequency; 24B (upperpanel) incontinence frequency; 24B (lower panel) Nocturia episodes.

FIG. 25 shows average foot stimulation intensity used by subjectsundergoing foot stimulation as described herein.

FIG. 26 shows a table of results of daily voiding from diaries insubjects who responded to foot stimulation as described herein.

FIG. 27 shows stimulation frequency and electrode placement used bysubjects undergoing foot stimulation as described herein.

FIG. 28 shows results of nocturia in subjects undergoing footstimulation as described herein.

DETAILED DESCRIPTION

The following description is merely exemplary in nature and is in no wayintended to limit the invention, its application, or uses. While thedescription is designed to permit one of ordinary skill in the art tomake and use the invention, and specific examples are provided to thatend, they should in no way be considered limiting. It will be apparentto one of ordinary skill in the art that various modifications to thefollowing will fall within the scope of the appended claims. The presentinvention should not be considered limited to the presently disclosedaspects, whether provided in the examples or elsewhere herein.

The use of numerical values in the various ranges specified in thisapplication., unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within. thestated ranges are both preceded by the word “about”. In this manner,slight variations above and below the stated ranges can be used toachieve substantially the same results as values within the ranges.Also, unless indicated otherwise, the disclosure of ranges is intendedas a continuous range including every value between the minimum andmaximum values. As used herein “a” and “an” refer to one or more.

As used herein, the electrodes and base are described as overlaying ananatomical feature. This means that the described electrodes or base arepositioned or configured/adapted for placement on skin superficial to(overlaying) a specific anatomical feature, such as an area of the foot,nerves and/or the bone(s) underlying the skin at that area of the foot.That is, the specified bone lies partially or wholly underneath the skinsaid to be overlaying the specified bone and/or nerve. Skin overlaying aspecified bone can overlap the specified bone and another bone. Tofacilitate description of the position of an electrode in the foot, the“anterior-to-posterior axis” of the foot is an axis extending from thetoes (anterior) to the heel (posterior) in an anterior to posteriordirection. Likewise, “medial,” “lateral,” “dorsal,” “plantar,”“superficial,” “proximal” and “distal” have their an-recognizedmeanings.

As used herein, the term “dorsal surface of the foot’ refers to the topsurface of the foot, including the ankle (talocrural) region andtalocrural joint.

As used herein, the term “plantar surface of the foot” refers to thesole, or bottom surface of the foot.

As used herein, the term “ball of the foot” refers to the plantarsurface of the foot, between the arch and the toes, around at least ananterior portion, e.g., the anterior 50%, of the metatarsals and themetatarsophalangeal joint.

As used herein, the term “forefoot” refers to the part of the foot (bothdorsal and plantar surface) including and superficial to the metatarsalsand proximal phalanges of the foot (FIGS. 1-2). This is the widest(medial to lateral) section of the foot. The medial longitudinal arch isthe medial arch of the foot, and includes the calcaneus, talus,navicular, cuneiform and the first through third metatarsal. Itsposterior portion includes the calcaneus and talus bones, and the medialand lateral plantar nerves enter the sole of the foot from the ankle atthis point.

As used herein, the term “midfoot” refers to the part of the foot (bothdorsal and plantar surface) including and superficial to the cuboid,navicular, and/or cuneiform bones (FIGS. 1-2).

As used herein, the term “hindfoot” refers to part of the foot (bothdorsal and plantar surface) including and superficial to the talusand/or calcaneus bones, and/or the talocrural joint (FIGS. 1-2).

As used herein, the term “predominance” means more than 50%, for examplewhen it is stated that an electrode of the electrode-containing devicedescribed herein overlays a predominance of the superficial peronealnerve and branches thereof, for example of the dorsal intermediate anddorsal medial cutaneous nerves or the lateral and medial plantar nervesin the forefoot, the electrodes cover an amount of skin on the dorsal orplantar surface of the foot that overlays at least 50% of thesuperficial peroneal or lateral and medial plantar nerves and branchesthereof (e.g., with regard to the peroneal nerve, the dorsalintermediate and dorsal medial cutaneous nerves), deep peroneal nerve,sural nerve, and saphenous nerve (FIGS. 3-4) at a given position in theanterior to posterior axis of the foot (e.g., on a frontal (coronal)plane) of the forefoot.

The ranges provided herein, for example and without limitation electricpulse frequencies, are based on experimentation on humans as well ascats. The frequencies necessary to elicit a desired response in humansand cats are very similar. As illustrated in U.S. Pat. No. 7,047,078,stimulation of the pudendal nerve in human subjects produce similarresults as compared to the results in cats. As such, frequency rangesapplicable to cats are considered to be effective in humans.

The devices, systems, and methods described herein provide a stimuluseffective to inhibit bladder contractions and are expected to affecturological conditions including: overactive bladder (OAB) symptomsincluding bladder overactivity, urinary frequency, urinary urgency,urinary incontinence (including bedwetting), interstitial cystitis (IC),urinary retention, and pelvic pain. The devices, systems, and methodsare also expected to affect gastrointestinal conditions, such as fecalincontinence, irritable bowel syndrome (IBS), and constipation. Forexample, sacral neuromodulation can treat both overactive bladder andurinary retention. In another example, transcutaneous stimulation of thetibial nerve approximately 10 cm above the ankle has shown some limitedpotential in alleviating urinary and fecal incontinence (see e.g.,Queralto et al. Preliminary results of peripheral transcutaneousneuromodulation in the treatment of idiopathic fecal incontinence Int JColorectal Dis (2006) 21: 670-672 and Vitton et al. TranscutaneousPosterior Tibial Nerve Stimulation for Fecal Incontinence inInflammatory Bowel Disease Patients: A Therapeutic Option? Inflamm BowelDis 2009; 15: 402-405), though these methods are sub-optimal becausethey require precise placement of the electrode over the tibial nerveand are not believed to stimulate substantially, if at all, any nervesin addition to the tibial nerve. It is believed that sacralneuromodulation modulates the central nervous system (CNS) bystimulating the sacral root and sending neural activity into the CNS.This neuromodulation input can balance the CNS, that is, if the bladderis overactive, the sacral neuromodulation will cause the CNS to inhibitbladder activity, but if the bladder is retaining too much urine, thenthe sacral neuromodulation will make the CNS more excitatory to thebladder.

The foot stimulation methods described herein, using the devices andsystems also described herein, are another type of neuromodulation thatis less invasive and less troublesome to the user. The devices andsystems send modulatory neural signal from the nerves of the foot to theCNS. The following examples show that neuromodulation caused bydelivering stimulation to the foot through at least one cathodal and atleast one anodal electrode can modulate the CNS to inhibit the bladder.This is not to say that foot neuromodulation can only induce inhibitoryeffects. When the pathological condition is the opposite (for example,urinary retention), foot neuromodulation at different intensities anddurations, or the same, should be able to modulate the CNS to facilitatebladder contraction or facilitate voiding. In summary, foot stimulationis another type of neuromodulation that can induce either inhibitory orexcitatory effect depending on the state of the CNS (that is, excitingor inhibiting an organ). As the following examples show, stimulation ofnerves of the foot (somatic nerve) can modulate the bladder (autonomicorgan). Therefore, it is logical and reasonable to conclude that suchstimulation will also modulate other autonomic organs, for example inthe gastrointestinal system.

It should also be recognized that the optimal electrical stimulationparameters to elicit a desired effect may vary to some degree fromsubject-to-subject, depending on a number of factors. Optimalfrequencies to elicit the desired goals can be adjusted fromperson-to-person. A “patient” may be human or animal and unlessspecified otherwise embraces a specific patient, a class of patients orany human or animal in a generic sense and does not imply anydoctor-patient relationship. Thus, a structure configured to, or adaptedto, a patient's foot includes structures configured to a specificpatient and/or a group of patients.

Subject to the limitations presented herein, any positioning ofelectrodes on the foot (at or below the ankle (talocrural) joint of apatient, on the dorsal (top) surface of a foot or the plantar (bottom))that is useful in modulating urological, bladder, gastrointestinal,and/or rectal contractions/activity should be considered within thescope of the present devices, systems, and methods, and slightalterations of the specific positioning described below should also beconsidered to be within the scope of the described devices, systems, andmethods.

Provided herein is an electrode-containing device for stimulating atleast a portion of the superficial peroneal nerve and branches thereof(e.g. dorsal intermediate and dorsal medial cutaneous nerves), deepperoneal nerve, sural nerve, and/or saphenous nerve of a patient. Theelectrodes include a posterior (first) electrode and an anterior(second) electrode. The first electrode is positioned on the dorsalsurface of the foot to stimulate the superficial peroneal nerve andbranches thereof (e.g. dorsal intermediate and dorsal medial cutaneousnerves), deep peroneal nerve, and/or saphenous nerve at a portion of thefoot overlaying at least a portion of the talus and/or calcaneus bones,as the superficial peroneal nerve, deep peroneal nerve, and/or saphenousnerve passes over the calcaneus and/or talus bones from the medial sideof the foot/ankle to the dorsal surface of the foot. Thus, the firstelectrode is positioned on the dorsal surface of the foot and/or thetalocrural joint to overlay at least a portion of the talocrural joint,at least a portion of the calcaneus bone and/or at least a portion ofthe talus bone (FIGS. 1 and 3). In some aspects the first electrode maybe positioned on the lateral surface of the talocruralregion/talocurural joint, to overlay the sural nerve. In other aspectsthe base is shaped such that the first electrode overlays the skincovering the superficial peroneal nerve, deep peroneal nerve, saphenousnerve, and/or sural nerve.

The second (anterior) electrode is sized and positioned to overlayapproximately 50% or more of the branches of the superficial peronealnerve and branches thereof (e.g. dorsal intermediate and dorsal medialcutaneous nerves), deep peroneal nerve, sural nerve, and/or saphenousnerve at the midfoot or forefoot, for example and without limitationspanning at least 50% of the width of the foot at its placement point onthe anterior-posterior axis of the foot (FIGS. 1, 3). Thus, the secondelectrode overlays an anterior portion of the metatarsals, themetatarsophalangeal joint, and/or the proximal phalanges. In aspects,the second electrode of the device overlays, and provides stimulationto, at least 50% of the branches of the superficial peroneal nervebranches thereof (e.g. dorsal intermediate and dorsal medial cutaneousnerves), deep peroneal nerve, sural nerve, and/or saphenous nerve, forexample and without limitation, 50%, more than 50%, more than 60%, morethan 70%, more than 80% or more than 90% of the superficial peronealnerve branches (e.g. dorsal intermediate and dorsal medial cutaneousnerves), deep peroneal nerve, sural nerve, and/or saphenous nerve at agiven anterior-to-posterior position in the midfoot or forefoot, such asoverlaying the metatarsophalangeal joint (FIG. 1). In aspects, thesecond electrode of the device overlays 50% or more of the superficialperoneal nerve and branches thereof (e.g. dorsal intermediate and dorsalmedial cutaneous nerves), deep peroneal nerve, sural nerve, and/orsaphenous nerve (FIG. 3). In one aspect, the device overlays, and thusmay be used to stimulate, a nerve and branches of that nerve. Forexample, the device overlays the superficial peroneal nerve and branchesthereof, the dorsal intermediate and/or dorsal medial cutaneous nervesand branches thereof, the saphenous nerve and/or branches thereof, thedeep peroneal nerve and/or branches thereof, and the sural nerve and/orbranches thereof.

The base is adapted to a portion of the dorsal surface of the foot,meaning it has a two- or three-dimensional shape that permits andoptimally facilitates placement of the electrodes at specific positionson the dorsal surface of the foot as described herein. The base may havea perimeter shaped in any suitable manner to allow for electrodeplacement to stimulate the superficial peroneal nerve and branchesthereof (e.g. dorsal intermediate and dorsal medial cutaneous nerves),deep peroneal nerve, sural nerve, and/or saphenous nerve as describedherein, and to facilitate easy and reproducible placement of the device.The base may be shaped in any suitable manner to allow for electrodeplacement to stimulate the superficial peroneal nerve and branchesthereof (e.g. dorsal intermediate and dorsal medial cutaneous nerves),deep peroneal nerve, sural nerve, and/or saphenous nerve as describedherein, and to facilitate easy and reproducible placement of the device.One example of such an arrangement of electrodes is shown schematicallyin FIG. 5, panel A.

In aspects, the base is substantially shaped to overlay the dorsalsurface of a human foot, or a portion thereof, for example from thetalocrural joint to the proximal phalanges (FIG. 5, panel B). In otheraspects, the base is substantially shaped to overlay the dorsal surfaceof a human foot, from just anterior to the talocrural joint to themetatarsophalangeal joint. Those of skill in the art will appreciatethat the base can be of any size, and in one aspect is manufactured asan insert to match standard foot sizes so as to optimize placement ofthe electrodes and to facilitate proper placement of the device on thedorsal surface of the foot by a layperson (end-user). For example, thebase may be sized to correspond to United States shoe sizes 1-15 and/orUnited Kingdom shoe sizes 0-14. The base may also be sized in width fromA to G (and corresponding United Kingdom widths). The base may also beconfigured and/or contoured to account for any foot disorder that wouldbenefit from a modified base, so that the electrodes in the devicecomfortably overlay the areas for which stimulation provides maximaleffect in either stimulating or inhibiting bladder, gastrointestinal,and/or rectal contractions/activity.

In other aspects, the base may be any suitable size and configurationthat allows for the electrodes to cover the requisite percentage ornumber of branches of the superficial peroneal nerve and branchesthereof (e.g. dorsal intermediate and dorsal medial cutaneous nerves),deep peroneal nerve, sural nerve, and/or saphenous nerve. For example,the device may be substantially shaped as in FIG. 5, panels B and C,wherein the electrodes are contained within a two or three-dimensionalstructure that is configured to contour to the dorsal surface of thefoot to allow for close interaction between the electrodes and thedorsal surface of the foot. In other aspects, the base can be of anyshape or amount of material, for example an “I” shape, to allow forinclusion of electrodes of sufficient size while reducing the amount ofbase material needed. It should be noted that FIG. 5 is a schematic,illustrative figure, and should be treated as such. The possible rangeof coverage and shapes of the device is as described herein.

Also provided herein is an electrode-containing device for stimulatingat least a portion of the medial and lateral plantar nerves of apatient. The electrodes include a first (posterior) electrode positionedon the sole (plantar surface) of the foot to stimulate the medial andlateral plantar nerves at a posterior portion of the medial longitudinalarch of the foot as the nerves pass from the medial side of thefoot/ankle to the sole of the foot. Thus, the first electrode ispositioned on the sole of the foot to overlay a medial, anterior portionof the calcaneus bone and optionally a portion of the talus bone (FIGS.2, 4). A second (anterior) electrode is sized and positioned to overlaya plurality of, e.g., 50% or more of, the branches of the medial andlateral plantar nerves at the midfoot or forefoot, for example andwithout limitation spanning at least 50% of the width of the sole of thefoot at its placement point on skin of the sole of foot at the forefoot(FIGS. 1-4).

The second electrode in this aspect may overlay branches of either themedial or lateral planter nerve or branches of both. In aspects, thesecond electrode of the device overlays, and provides stimulation to, atleast 50% of the branches of the medial and lateral plantar nervebranches, for example and without limitation, 50%, more than 50%, morethan 60%, more than 70%, more than 80% or more than 90% of the medialand lateral plantar nerve branches at a given anterior-to-posteriorposition in the forefoot, such as overlaying the metatarsophalangealjoint, or ball of the foot (FIG. 2). In aspects, the second electrode ofthe device overlays 50% or more of the medial and lateral plantar nervebranches of the forefoot (FIG. 4). In one aspect, the device overlays,and thus may be used to stimulate, a nerve and branches of that nerve.For example, the device overlays the plantar nerve and branches of theplantar nerve, and/or the medial and/or lateral plantar nerves, andbranches thereof.

No matter whether the device described herein is designed to overlay thedorsal (FIGS. 5 and 7) or plantar (FIGS. 6 and 8) surface of the foot,the base may be formed of any material that provides comfort orminimizes discomfort, given that in aspects, the base is providedbetween the dorsal or plantar surface of an individual's foot and theindividual's footwear and/or garments (socks, hose, and the like). Inone aspect, the base is formed of a substantially or completelynon-conductive material. Such materials include: gels, foams, rubbers,cellulose-based materials, cellophanes, silicon-based products,polymers, neoprene, animal hides, leathers, polyethylene, ethyl vinylacetate, polypropylene, polyimide, polyester, polyethyleneterephthalate, polyaryletheretherketone, polytetrafluoroethylene,polyethylene naphthalate, co-polymer plastics, and combinations thereof,which are known to those of skill in the art. The base may optionallyinclude materials for added comfort, such as gels and the like, whichare also known to those of skill in the art. In aspects, the base may beformed of mixtures of suitable materials, either in an amalgamation in aone-piece construction or in discrete layers of one or more materials.In one aspect, the base is an orthotic, custom-designed for theindividual in need of the electrode-containing device (FIG. 8). Inanother aspect, the base has a thin profile, such as a thin film,membrane, or polymer, suitable for placement between the dorsal orplantar surface of an individual's foot and the individual's footwear orgarment, such a sock, legging, hose, or the like (FIGS. 7 and 8).

The base of the device includes at least two positions for placement ofelectrodes to provide the stimulation capable of modulating urological,bladder, gastrointestinal, and/or rectal activity (FIGS. 5-13). Withregard to the FIGS. 5-8, at least one electrode position, for the firstelectrode (10), is at a posterior portion of the base (50) of the deviceand at least one electrode position, for the second electrode (20), isat an anterior portion of the base. At least one of the electrodepositions is for a cathodal electrode, or an electrode that acts as acathode, and at least one of the electrode positions is for an anodalelectrode, or an electrode that acts as an anode. According to oneaspect, the second (anterior) electrode position, and electrode (20)that occupies said position, is of sufficient size such that it extendsover a predominance, or more than 50%, of the width of the forefoot. Inaspects, the base (50) also includes a connector (30), e.g., male orfemale plugs or other electrical connectors as are known in the art, forproviding direct electrical connection between the electrode-containingdevice and a pulse generator. The electrodes (10, 20) are connected to aconnector (30) via conductive leads (e.g., wires, traces, etc.) (40).Electrodes (10, 20) may each have a distinct lead connecting them to theconnector (30), or may be connected in series (i.e., only one leademerges from connector (30) to the electrodes).

In aspects, the electrodes (10, 20) are directly electrically connectedto a pulse generator, but a connector (30) at some point between thepulse generator and the electrodes is preferred so that the electrodeassembly can be replaced or exchanged. The connector (30) may be anylow-profile electric connector, male or female, suitable for use in alow-profile foot orthotic, thin film, or the like so as to preventdiscomfort to the patient when shoes are worn over the device.Non-limiting examples of such a low-profile connector may be see in U.S.Pat. No. 5,326,272. Low-profile electrical connectors are known to thoseof skill in the art. It may be preferable that leads (40) extend fromthe base of the device so that the connector (30) can be located invarious locations for comfort. The pulse generator may be connected tothe device through one or more wires, carrying a plurality of leads(i.e. at least one lead for the anode and at least one lead for thecathode).

The electrodes (10, 20) of the electrode-containing device reside on asurface of the base (50) that comes into contact with the dorsal(top—FIG. 5) or plantar surface (bottom—FIG. 6) of the foot duringnormal use. The electrodes are formed of a conductive material, suitablefor conducting electrical stimulation from the electrode-containingdevice through the skin of the individual to the nerves underlying theskin of the foot. Suitable materials for forming the electrodes of thebase include metals and metal foils, such as, for example and withoutlimitation, copper, gold, silver, tin, nickel, steel, cupronickel,nickel-cobalt ferrous alloys, and carbon-based materials. Those of skillin the art are aware of the typical constitution of electrodes suitablefor use with TENS (Transcutaneous Electrical Nerve Stimulation), NMES(Neuromuscular Electrical Stimulation), patterned ElectricalNeuromuscular Stimulation (PENS), and Interferential Current (IFC). Solong as the electrode is capable of delivering a suitable electricalcurrent to the skin of a patient when placed atop or underneath apatient's foot at a position described herein, it is considered to beuseful in the devices, systems, and methods described herein.

In aspects, the electrodes are replaceable electrodes. The electrodesmay be held in place in the base by any suitable mechanism, such as forexample and without limitation, by one or more snaps, snap connections,hook and loop connections, Velcro®, disposable and/or reusable adhesivesthat allow for removable adhesion of the device to a patient's foot, andthe like. By way of non-limiting example, areas of adhesive placementfor the device described herein may be seen between the hashed lines andthe outline of the base in FIGS. 5 and 6. The adhesive may be conductiveor non-conductive. In aspects, the adhesive is non-conductive. The useof a non-conductive adhesive such as described herein for removablyadhering the base to a patient's foot maintains a discrete area ofstimulation. By removably adhering it is meant that the adhesive issufficient to maintain the base in a position for stimulation to theindicated areas during walking and movement of the individual, but isnot so strong so as to cause injury and/or substantial pain duringremoval of the base from the foot, or to damage clothing/garments duringremoval.

Those of skill in the art will appreciate and have knowledge of suitablemeans for holding the electrode in place in the base material, and willunderstand that the amount of adhesive and type of adhesive that issuitable for holding the device in place, on the foot of the patient orin the footwear of the patient, can be adjusted. Non-limiting examplesof medically-acceptable adhesives include: adhesives used on bandages,medical tapes (such as those manufactured by 3M, St. Paul, Minn., USA),including those formed of silicone or cloth, Soft-Pro™ Silicone Gel,Acrylics, and PU Gel manufactured by Scapa Healthcare (Liverpool, N.Y.,USA and Inglewood, Calif., USA), Uro-Bond® III Adhesive, manufactured byUrocare (Pomona, Calif., USA), and the like known to those of skill inthe art). In other aspects, the device may comprise and be held in placeby elastic bands, or bands that may connect through snap connections,hook and loop connections, Velcro®, and the like. The bands can encirclethe dorsal or plantar portion of the foot and connect there by anysuitable means. For example, and without limitation, FIG. 13 shows oneaspect of a device that is configured for placement on the plantarsurface of a patient's foot. In other aspects, the device includesmaterial that fits between toes/phalanges of the wearer's foot forsupporting the device in place addition to any support provided byfootwear or garments).

In aspects, the electrodes include a conductive gel or paste forincreasing conductance and/or reducing impedance/resistance between theelectrode and the foot of the patient. For example, and withoutlimitation, conductive gels/pastes may be provided within the hashedline portion shown in FIGS. 5 and 6. Suitable conductive gels are knownto those of skill in the art. For example and without limitation, asuitable conductive gel is Spectra 360 Electrode Gel manufactured byParker Labs (New Jersey, USA) or Ten20 EEG Conductive Paste manufacturedby Weaver and Company (Colorado, USA). In aspects in which theelectrodes are replaceable, the electrodes may be pre-packaged with anamount of conductive gel or paste. According to one aspect, theconductive gel has adhesive properties, for example Ten20 EEG ConductivePaste (Weaver and Company, Colorado, USA), Tensive Conductive AdhesiveGel (Parker Labs, New Jersey, USA), and the like, which are known tothose of skill in the art. In aspects, the conductive gel or pastesurrounds an electrode center and is encapsulated by a conductivematerial, such that gel/paste is able to improve conductivity/decreaseimpedance/resistance without causing spillage of the conductivegel/paste onto the patient's foot or garments. In aspects in which theelectrodes do not come pre-packaged with gel, the patient may apply suchgel/paste each day before the electrode-containing device is applied tothe foot.

The electrodes of the electrode-containing device are spaced-apart andoriented by configuration of the electrodes on the base. The electrodesare attached to the base, meaning they are affixed to a surface of, orpartially or completely embedded within the base, leaving a functionalsurface of the electrode exposed for skin contact. The size andpositioning of the electrodes in the base is based on the relativelocation of anatomical features of the dorsal or plantar surface of thefoot, and depends on the size of an individual's foot, and, optionally,based on the specific contours of an individual's foot or a foot of atypical individual. In certain aspects, the configuration of theelectrodes within the device provides electrical stimulation to at leasta portion of the forefoot and/or midfoot and at least a portion of thehindfoot and/or talocrural region/talocrural joint. Exemplaryarrangements of electrodes on an electrode-containing devices are shownin FIGS. 5-13. In aspects, the electrodes overlay at least a portion ofthe metatarsophalangeal joint and at least a portion of the calcaneusand/or talus bones. Any arrangement of electrodes in which stimulationcan be provided to the nerves of the foot, particularly to apredominance of the superficial peroneal nerve and branches thereof(e.g. dorsal intermediate and dorsal medial cutaneous nerves), deepperoneal nerve, sural nerve, saphenous nerve, and/or the lateral and/ormedial plantar nerves is contemplated by the present invention. Asprovided above, at least one of the electrodes acts as a cathode and atleast one of the electrodes acts as an anode. That is, the flow ofelectrons from the electrode-containing device of the present inventionis from anode, through the tissue of the foot, to the cathode.

In aspects, the at least one cathode is the anterior electrode andoverlays at least a portion of the forefoot and/or midfoot, and the atleast one anode is the posterior electrode and overlays at least aportion of the hindfoot and/or talocrural joint. In other aspects, thecathode overlays at least a portion of the metatarsophalangeal joint andthe anode overlays at least a portion of the talus and/or calcaneusbones. The opposite configuration may also be suitable for providingelectrical stimulation in accordance with the present invention. Thatis, the anode may be the anterior electrode and may overlay at least aportion of the forefoot and/or the metatarsophalangeal joint and thecathode may be the posterior electrode and overlay at least a portion ofthe talus and/or calcaneus bones.

Without wishing to be bound by this theory, the device, system andmethod described herein stimulate the superficial peroneal nerve andbranches thereof (e.g. dorsal intermediate and dorsal of the tibialnerves, namely the medial cutaneous nerves), deep peroneal nerve, suralnerve, and/or saphenous nerves. In aspects, the device, system andmethod described herein stimulate the medial and/or lateral plantarbranches of the tibial nerve.

The electrodes of the electrode-containing device described hereinprovide electrical pulses effective to modulate urological, bladder,gastrointestinal, and/or rectal activity. In one aspect, the stimulationprovided by the device inhibits bladder contractions. This is thought toproduce a storage stage, similar to the typical storage stage of thenormal micturition or defecation processes. As will be recognized by aperson of skill in the art, characteristics of electrical pulse,including, without limitation, amplitude (pulse strength, referring tothe magnitude or size of a signal voltage or current), voltage,amperage, duration, frequency, polarity, phase, relative timing andsymmetry of positive and negative pulses in biphasic stimulation, and/orwave shape (e.g., square, sine, triangle, sawtooth, or variations orcombinations thereof) may be varied in order to optimize results in anyparticular subject or class of subjects. Subjects may be classified byspecies, disease/condition, sex, or any other factor that can begeneralized to a group. Stated ranges are intended to include all valuesand ranges within the stated ranges. So long as other characteristics ofthe electrical signals (e.g., without limitation, amplitude, voltage,amperage, duration, polarity, phase, relative timing and symmetry ofpositive and negative pulses in biphasic stimulation, and/or wave shape)are within useful ranges, modulation of the pulse frequency will achievea desired result. Useful values for those other characteristics arewell-known in the art and/or can be readily established by routineexperimentation.

One characteristic of the electrical signals used to produce a desiredresponse, as described above, is pulse frequency. Although effectiveranges (e.g., frequencies able to produce a stated effect) may vary fromsubject-to-subject, and the controlling factor is achieving a desiredoutcome, certain, non-limiting exemplary ranges may be as follows. Forinhibiting bladder or bowel contractions, those frequencies may rangefrom approximately 1 Hz (Hertz, or pulses per second) to approximately500 Hz, though in practice, the range may be more typically 1-50 Hz, therange typically used for human nerve stimulation. Data below shows arange of at least from 5-20 Hz, with 5 Hz pulses being preferred in someinstances. Useful pulse durations (pulse widths) typically range from0.01 to 3.0 ms (milliseconds), for example 0.2-1.0 ms or 1 ms pulses.

Another characteristic of the pulses are the voltage. Nerve stimulationcan be achieved in a typical range of from 1-100 V, for example 3-16 Vas shown in the examples below, with a range of from 1 to 20 V beingpreferred in many instances. The typical voltage for foot stimulationmay be from 2 to 6 times the toe twitch motility threshold (2 T-6 T),where the pulses cause toe twitching.

Yet another characteristic of the pulses is the current that is appliedto produce the stimulation that is capable of modulating urological,bladder, gastrointestinal, and/or rectal activity. Stimulation can beachieved in a typical range of from 1 milliamperes (mA) to 80 mA. Asshown in the examples below, a range of 15 mA to 60 mA, or 25 mA to 60mA is preferred in many instances for providing the range of 2 T to 6 Tdesired in one aspect.

As indicated above, the waveform of the pulses may vary, so long as thedesired effect is realized. One skilled in the art will appreciate thatother types of electrical stimulation may also be used in accordancewith device, system and methods described herein. Monophasic or biphasicstimuli, or a mixture thereof may be used. Damage to nerves by theapplication of an electrical current may be minimized, as is known inthe art, by application of biphasic pulses or biphasic waveforms to thenerve(s), as opposed to a monophasic pulses or waveforms that can damagenerves in some instances of long-term use. “Biphasic current,” “biphasicpulses” or “biphasic waveforms” refer to two or more pulses that are ofopposite polarity that typically are of equal or substantially equal netcharge (hence, biphasic and charge balanced) and may be symmetricalasymmetrical or substantially symmetrical. This is accomplished, forexample, by applying through an electrode one or more positive pulses,followed by one or more negative pulses, typically of the same amplitudeand duration as the positive pulses, or vice versa, such that the netcharge applied to the target of the electrode is zero or approximatelyzero. The opposite polarity pulses may have different amplitudes,profiles or durations, so long as the net applied charge by the biphasicpulse pair (the combination of the positive and negative pulses) isapproximately zero.

The waveform may be of any useful shape, including without limitation:sine, square, rectangular, triangle sawtooth, rectilinear, pulse,exponential, truncated exponential, damped sinusoidal. The pulses mayincrease or decrease over the stimulus period. In aspects, the waveformis rectangular. The pulses may be applied continuously or intermittentlyas needed. As indicated below, stimulation of the foot at certainvoltages for certain time periods elicits post-stimulus inhibition ofbladder contractions. Therefore, the stimulus may be applied for shortintervals (e.g. 1-10 minutes) or longer intervals (up to 360 minutes) toachieve longer-lasting relief, in terms of hours or days. In certainaspects, the stimulus is applied for at least 15, 30, 45, 60, 75, 90, ormore minutes. The stimulus may be applied intermittently (that is, thepulses are turned on and off alternately during a stimulus interval forany time period) during continuous or interval stimulus protocols. Forexample, the stimulus may be applied for 5 seconds on and 5 seconds offover an interval of, for example, 1-10 minutes or longer. Other examplesof intermittent application of pulses may be 1-90 seconds on and 1-90seconds off over up to a 360 minute time period. So long as other pulseparameters are within acceptable limits, the inhibition is temporary anddoes not damage the involved nerves. For example, intermittentapplication of pulses may be continuous, that is, for as long as thepulses are having the desired effect, and for as long as the patientdesires (i.e., is not painful or harmful to the patient). A benefit ofstimulating the dorsal surface of the foot, compared to stimulation ofthe plantar surface of the foot, is that continuous stimulation is notneeded when the dorsal surface of the foot is stimulated. This increasescomfort and patient compliance. However, in one aspect, the stimulationis provided continuously, for example to treat severe symptoms, or anysymptom that does not respond to intermittent, short-term stimulation tothe degree desired by a clinician or the patient. Additionally, the fullweight of the patient's body does not bear on the electrodes, which canreduce discomfort compared to placement of electrodes on the plantarsurface.

In another aspect, a system for use in inhibiting in a patient one ormore of: bladder contractions, rectum contractions, urination (includingbedwetting), defecation, and pelvic pain of the bladder, urethra,prostate, anus or rectum is provided. The system comprises theelectrode-containing device essentially as described above and a pulsegenerator unit, in communication with the device, configured to produceelectric pulses able to modulate urological, bladder, gastrointestinal,and/or rectal activity, such as inhibition of bladder contractions. Asindicated above, the frequency ranges from 1 Hz to 500 Hz, such as 1-50Hz, 5-20 Hz, or 5 Hz. Voltage may range from 1-100 V, such as from 1-20V or from 3-16 V. Current may range from 1 mA to 80 mA. Theaforementioned parameters may be adjusted to provide a stimulus that isfrom 2 to 6 T, and may be activated for from 1 minute to 360 minutes.The system may be set to produce pulses continuously or intermittentlyas described above, and can be controllable by the patient, healthcareprovider, or both. As described previously, because the electrodes areplaced on the dorsal surface of the foot, continuous stimulation of thesuperficial peroneal nerve is not required (though it may be employed)to achieve the desired effect of modulating urological gastrointestinalactivity.

In practice, the pulse generator may be programmable, pre-programmed,non-programmable, or otherwise adapted to or configured to producepulses within the ranges described herein as being useful for the statedpurposes of modulating urological, bladder, gastrointestinal, and/orrectal activity. For example, a commercial multi-purpose electricalstimulator for use in, e.g., TENS or NEMS, may be adjusted to theparameters useful in the methods described herein. In one non-limitingexample, the device is non-programmable, having a pre-fixed output forvoltage, pulse frequency, pulse length, and/or stimulus pattern/intervalthat cannot be changed. For instance, in one aspect, the pulse generatorproduces 0.2 ms pulses at 5 Hz and between 25 and 60 mA for 90 minuteswhenever the device is activated either by the patient or another, or atspecific intervals, for example hourly, every 90 minutes, every 120minutes, or longer. In aspects, the stimulation occurs for discreteperiods 1 or more times per day, for example three times per day for 30minutes each period. Other settings may be any useful stimulationparameters within the ranges described above as being useful in themethods described herein. In another example, the device has two or morepre-fixed settings that cannot be changed, so that a patient or healthcare provider can choose the most effective stimulation parameter forthe patient or for the patient's particular circumstances (e.g., in ameeting versus before bed). The frequency may be adjustable or achievedin any manner within any range described herein. Programmable orfixed-output electrical pulse generators are common and configuration tothe stimulation parameters described herein is well within the abilitiesof those of ordinary skill in the art. For example, and withoutlimitation, U.S. Pat. Nos. 5,273,033; 3,881,494; and 3,902,502 describesuitable pulse generators.

The system further includes a controller for providing instructions tothe pulse generator. The controller may be a wireless controller, forproviding control instructions to the pulse generator. In such aspects,the pulse generator includes a first wireless communication system andthe controller includes a second wireless communication system, aninput, and an optional display. In one aspect, the electric pulses aremonophasic. The first wireless communication system may also transmitstatus information for the pulse generator to the wireless controller.Further description of one aspect of such a system is described inreference to FIGS. 9-13. The phrases “configured to” and “adapted to”and like terms or phrases refer to the manufacture, production,modification, etc. of a device or system to produce a desired function.In the context of the devices or systems described herein, a device orsystem “adapted to” or “configured to” produce a desired output is adevice programmed of otherwise manufactured, produced, or modified inany manner to produce the stated effect. In the context of an electrodeassembly as described herein, the device may be “adapted to” and“configured to” a specified anatomical structure, such as the forinstance the physical size and shape of the sole of the foot or aportion thereof, such as the profile of an arch, heel, ball of the foot,toes or foot pad. Additionally, when it is stated that the base isconfigured to interact with the dorsal or plantar surface of a humanfoot, it is meant that the base is shaped, sized, and contoured in amanner that allows for a close tactile relationship between the surface(including electrodes) of the base and the top (dorsal) or bottom(plantar) surface of the foot, to allow for good conduction ofelectrical pulses from electrodes to the nerves underlying the skin.

Turning to FIGS. 9 and 10, depicted schematically are aspects of asystem for stimulating foot nerves according to the device and methodsdescribed herein. Structures are out of proportion to facilitateillustration of elements of the depicted system. Pulse generator 100 isdepicted as having one output channel, though an increased number ofoutput channels falls within the scope and spirit of the invention. Wire120 is attached by leads 160 and 170 to electrodes 140 and 150, whichare integrated into the base 130 of the electrode-containing device 110on the dorsal surface of the foot across the forefoot/midfoot (electrode140) and hindfoot region (electrode 150) of a foot 200. In aspects, onlya single, multi-conductor wire 120 connects pulse generator 100 to theleads 160, 170 of electrode-containing device 110 through connector 190,but the single wire contains at least a plurality of leads, forconnecting to the anode and cathode. Another aspect (not shown), employsa plurality of wires, one carrying lead(s) for cathode(s) and otherscarrying lead(s) for anode(s) rather than single wire 120. In the aspectof FIG. 9, electrode 140 is shown on the dorsal surface of the foot atthe midfoot and/or forefoot while electrode 150 is shown at thehindfoot.

Output parameters of the pulse generator 100 can be controlled via awired interface, but also may be controlled by wireless transmission, asshown in the aspect of FIG. 9, which can be carried any suitablewireless protocol, such as radio frequency, IEEE 802.11a/ac/b/g/n,Bluetooth, ZigBee (IEEE 802.15), etc. Thus, an external controller 300is depicted for communicating with the pulse generator 100. Externalcontroller 300 is depicted as having a display 320, such as an LCD, LEDor OLED display, and a keypad 340 for entering data into the externalcontroller 300. External controller is depicted as sending a wirelesstransmission 360 to pulse generator 100, though in another aspect, datacan be transferred both to the pulse generator 100 from the externalcommunicator 300 and vice-versa, to permit monitoring of one or moreparameters of pulse generator 100, including, without limitation, outputsignal characteristics (e.g., frequency, amplitude, etc. as outlinedabove) and battery strength. Smartphones, tablets or computers may beused as controllers, software, such as iOS, Android or Windows-based“apps” may be developed to act as controllers for these devices.

Likewise, wireless transmission 360 can be replaced by a wire or otherconductor. Activity of pulse generator 100 and external controller 300typically is microprocessor controlled and software/firmware installedonto the pulse generator 100 and external controller 300 hardware may beused to implement the described tasks, and to provide, for example andwithout limitation, a graphical user interface (GUI) for the display320, which facilitates use of the system. Both pulse generator 100 andexternal controller 300 may comprise any suitable electrical andelectronic components to implement the pulse, communication, feedback,adjustment, etc. activities, including, microprocessors, memory (e.g.,RAM, ROM. Flash memory, etc.), connectors, batteries, powertransformers, amplifiers, software (including, for example and withoutlimitation: firmware, operating systems, utilities, processes,routines), etc. A person of skill in the electronic arts will be able toimplement such a system using readily-available electronics parts andordinary programming skills. Proprietary chips, chipsets, etc. may bedesigned and manufactures to implement the devices described herein.Elements of the system depicted in. FIG. 9, such as a battery and apulse generator can be integrated into an aesthetically-pleasinghousing, such as an anklet, such as is schematically illustrated in FIG.10.

With continuing reference to FIG. 9, pulse generator 100 may beconnected (at 190) to electrode-containing device 110 through anysuitable connection that can transmit pulses provided by pulse generator100 to the device 110 abutting the dorsal surface of an individual'sfoot 200. Pulse generator 100 and electrode-containing device 110 may bepermanently connected through wiring, or through a releasable coupling.Pulse generator 100 may be a device that can be attached to theindividual wearer's ankle, shoe, or any other suitable place for thepulse generator 100 to provide the pulses necessary to stimulate thenerves of the foot through electrode-containing device 110.

The external controller 300 may be a proprietary device that isspecifically designed for the task, or a non-proprietary device, such asa commercial TENS controller, smart phone, tablet, personal computer ora portable computer. Pulse generator 100 may comprise any number ofchannels, so long as the number of channels needed to implement adesired method is provided.

With continuing reference to the system of the present invention, FIG.10 shows a side view of one aspect of the system, includingelectrode-containing device 110, base 130, electrodes 140, 150, andpulse generator 100. A controller (not shown) may provide instructionsto pulse generator to provide sufficient stimulation through wire 120containing leads for anode and cathode to stimulate nerves of the foot200. Pulse generator 100 may be a device that is suitable for attachmentaround the ankle or lower leg of a patient, such that it can bedisguised/hidden from view while still providing stimulation to thepatient's foot 200. Wire 120 containing leads may be placed between thewearer's leg/ankle and a garment (sock, hose, or the like) for a thinfilm-type electrode-containing device (not shown) or for a flexible orrigid two or three-dimensional structure, or may overlay a garment(sock, hose, or the like) for a flexible or rigid two orthree-dimensional structure 110.

Returning to FIG. 9, a potential difficulty with use of wireless devicessuch as a wireless controller for communicating instructions to a pulsegenerator capable of receiving wireless instructions is one of identity.A controller 300 should only be able to control one pulse generator 100to prevent accidental stimulation of unintended subjects, or evenintentional stimulation. In its simplest form, the transmission range ofthe devices can also be limited to prevent transmission over distancesmore than a few feet, thereby limiting the chances of unintendedstimulation (crosstalk). Also, any number of identity verificationmechanisms may be utilized to prevent crosstalk. In one aspect,different transmission wavelengths may be used for different devices,thus lowering the likelihood of crosstalk. In another aspect, the pulsegenerator 100 is programmed to only respond to a transmission containinga pre-defined signal, such that the pulse generator 100 and externalwireless controller 300 must first, and/or periodically “handshake” inorder to communicate. Likewise, the pulse generator 100 and/orcontroller 300 may transmit encrypted signals which only can bedecrypted by a key stored in the other of the pulse generator 100 and/orcontroller 300. In another aspect, RID tagging technology may be used toensure that the controller 300 and pulse generator 100 match. Anycombination of these proximity and/or identity verification measures maybe used to prevent cross-talk. Other useful technologies for ensuringsecurity and identity in communication are, or may be available and areequally applicable.

Turning to FIGS. 11-13, depicted schematically is one aspect of a systemfor stimulating foot nerves according to the device and methodsdescribed herein. Structures are out of proportion to facilitateillustration of elements of the depicted system. Pulse generator 100 isdepicted as having one output channel, though an increased number ofoutput channels falls within the scope and spirit of the invention. Wire120 is attached by leads 160 and 170 to second electrode 140 and firstelectrode 150, respectively, which are attached to (e.g., affixed to,embedded in or integrated into) the base 130 of the electrode-containingdevice 110, and are thereby adapted to the plantar side of the footacross the forefoot region (electrode 140) and hindfoot region(electrode 150) of a foot 200. In the depicted aspect, only a single,multi-conductor wire 120 connects pulse generator 100 to the leads 160,170 of electrode-containing device 110 through connector 190, but thesingle wire contains at least a plurality of leads, for connecting tothe anode and cathode. Another aspect (not shown), employs a pluralityof wires, one carrying lead(s) for cathode(s) and others carryinglead(s) for anode(s), rather than single wire 120. In the aspect of FIG.11, electrode 140 is shown on the plantar side of the foot at theforefoot while electrode 150 is shown at the hindfoot.

Output parameters of the pulse generator 100 can be controlled via awired interface, but also may be controlled by wireless transmission, asshown in the aspect of FIG. 11, which can be carried any suitablewireless protocol, such as radio frequency, IEEE 802.11a/ac/b/g/n,Bluetooth, ZigBee (IEEE 802.15), etc. Thus, an external controller 300is depicted for communicating with a receiver in the pulse generator100. External controller 300 is depicted as having a display 320, suchas an LCD, LED or OLED display, and a keypad 340 for entering data intothe external controller 300. External controller is depicted as sendinga wireless transmission 360 to pulse generator 100, though in anotheraspect, data can be transferred both to the pulse generator 100 from theexternal communicator 300 and vice-versa, to permit monitoring of one ormore parameters of pulse generator 100, including, without limitation,output signal characteristics (e.g., frequency, amplitude, etc. asoutlined above) and battery strength. Smartphones, tablets or computersmay be used as controllers, software, such as iOS, Android orWindows-based “apps” may be developed to act as controllers for thesedevices.

Likewise, wireless transmission 360 can be replaced by a wire or otherconductor. In such a case, the controller may be housed within the samehousing as the pulse generator. Activity of pulse generator 100 andexternal controller 300 typically is microprocessor controlled andsoftware/firmware installed onto the pulse generator 100 and externalcontroller 300 hardware may be used to implement the described tasks,and to provide, for example and without limitation, a graphical userinterface (GUI) for the display 320, which facilitates use of thesystem. Both pulse generator 100 and external controller 300 maycomprise any suitable electrical and electronic components to implementthe pulse, communication, feedback, adjustment, etc. activitiesincluding, microprocessors, memory (e.g., RAM, ROM. Flash memory, etc.),connectors, batteries, power transformers, amplifiers, software(including, for example and without limitation: firmware, operatingsystems, utilities, processes, routines), etc. A person of skill in theelectronic arts will be able to implement such a system usingreadily-available electronics parts and ordinary programming skills.Proprietary chips, chipsets, etc. may be designed and manufactures toimplement the devices described herein. Elements of the system depictedin FIG. 11, such as a battery and a pulse generator can be integratedinto an aesthetically-pleasing housing, such as an anklet, such as isschematically illustrated in FIG. 12.

With continuing reference to FIG. 11, pulse generator 100 may beconnected (at 190) to electrode-containing device 110 through anysuitable connection that can transmit pulses provided by pulse generator100 to the device 110 abutting the plantar surface of an individual'sfoot 200. Pulse generator 100 and electrode-containing device 110 may bepermanently connected through wiring, or through a releasable couplingor connector. Pulse generator 100 may be a device that can be attachedto the individual wearer's ankle, shoe, or any other suitable place forthe pulse generator 100 to provide the pulses necessary to stimulate thenerves of the foot through electrode-containing device 110.

The external controller 300 may be a proprietary device that isspecifically designed for the task, or a non-proprietary device, such asa commercial TENS controller, smart phone, tablet, personal computer ora portable computer. Pulse generator 100 may comprise any number ofchannels, so long as the number of channels needed to implement adesired method is provided.

With continuing reference to the system of the present invention, FIG.12 shows a side view of one aspect of the system, includingelectrode-containing device 110, base 130, electrodes 140, 150, andpulse generator 100. A wireless controller (not shown) may provideinstructions to pulse generator to provide sufficient stimulationthrough wire 120 containing leads for the anode and cathode to stimulatenerves of the foot 200. Pulse generator 100 may be a device that issuitable for attachment around the ankle or lower leg of a patient, suchthat it can be disguised/hidden from view while still providingstimulation to the patient's foot 200. Wire 120 containing leads may beplaced between the wearer's leg/ankle and a garment (sock, hose, or thelike) for a thin film-type electrode-containing device (not shown), ormay overlay a garment (sock, hose, or the like) for an orthotic-typeelectrode containing device 110.

Returning to FIG. 11, a potential difficulty with use of wirelessdevices such as a wireless controller for communicating instructions toa pulse generator capable of receiving wireless instructions is one ofidentity. A controller 300 should only be able to control one pulsegenerator 100 to prevent accidental stimulation of unintended subjects,or even intentional stimulation. In its simplest form, the transmissionrange of the devices can also be limited to prevent transmission overdistances more than a few feet, thereby limiting the chances ofunintended stimulation (crosstalk). Also, any number of identityverification mechanisms may be utilized to prevent crosstalk. In oneaspect, different transmission wavelengths may be used for differentdevices, thus lowering the likelihood of crosstalk. In another aspect,the pulse generator 100 is programmed to only respond to a transmissioncontaining a pre-defined signal, such that the pulse generator 100 andexternal wireless controller 300 must first, and/or periodically“handshake” in order to communicate. Likewise, the pulse generator 100and/or controller 300 may transmit encrypted signals which only can bedecrypted by a key stored in the other of the pulse generator 100 and/orcontroller 300. In another aspect, RFID tagging technology may be usedto ensure that the controller 300 and pulse generator 100 match. Anycombination of these proximity and/or identity verification measures maybe used to prevent cross-talk. Other useful technologies for ensuringsecurity and identity in communication are, or may be available and areequally applicable.

With regard to FIGS. 13 and 14, shown therein are one aspect of a deviceand system according to the present invention. FIG. 13 shows a small,inexpensive, and easy-to-use stimulator for foot neuromodulation,including two units: a disposable unit and an electronic unit. Thedisposable unit (a) has an insole shaped substrate or base (130) made ofa soft, transparent polymer, which serves multiple purposes, includingto match different sizes of the foot, and to pre-fix the electrodelocations. Two electrodes (140, 150) are included, and can be formed of,for example and without limitation, copper foils plated withsilver-silver chloride. These electrodes can be heat-printed on thesurface of the substrate (base) (130). In this aspect, each of theelectrodes (140, 150) are connected to an electrode connector (190),made of a thick, high-quality paper.

The connector (190) can be folded along a perforated line (197) to beconnected with a strap (199) in the electronic unit (b) (100) using asnap button (195). The silver-silver chloride surface of each electrodecan be pre-applied with a conductive adhesive, forming a properelectrical interface with the skin enabling an effective stimulation ofthe tibial nerve (or branches thereof, as described herein). In theillustrated aspect, the electronic unit (b) (100) is located on top ofthe foot. On the top panel (not shown) of the electronic unit (100),there can be three main components: a switch/potentiometer combo to turnon/off the power and control the stimulation strength, two LED lightsindicating the power and working status of the system, and a timerswitch which, when activated, automatically stops stimulation after apre-set period of time. On the side panel of electronic unit (100),there can be located a standard or mini USB socket (not shown) forrecharging the battery (for example, lithium-ion) inside the electronicunit (100). The straps (199) have three functions: 1) making anelectrical connection to the electrodes (140, 150), 2) securing theinsole (substrate—130) and the electronic unit (100), and 3)facilitating observation and hand access to the top panel for adjustingthe stimulation strength.

The block diagram of the circuitry within the electronic unit is shownin FIG. 14. In the illustrated aspect, a non-linear oscillator producesa square wave of a desired frequency. A timer controls the oscillatorfor automatic shutdown. The square wave is processed by the pulseshaping circuit producing a signal with narrow pulses. A potentiometercontrols the pulse width which, when the signal passes through thestep-up transformer, can also effectively control the strength of thestimulation. The power amplifier provides a sufficient signal power todrive the step-up transformer. With a 3.7 V, 500 mAh lithium-ionrechargeable battery as the power supply, the device can produce 5 Hz,approximately 0.2 ms stimulation pulses with adjustable peak amplitudebetween 0-100 V.

Also provided herein is a method of using the electrode-containingdevice, including the other components of the system such as a pulsegenerator and controller, for stimulating a physiological response in asubject, such as modulation of urological, bladder, gastrointestinal,and/or rectal activity, for example one or more of: overactive bladder(OAB) symptoms including bladder overactivity, urinary frequency,urinary urgency, urinary incontinence (including bedwetting),interstitial cystitis (IC), urinary retention; pelvic pain; fecalincontinence; irritable bowel syndrome (IBS); and constipation. Themethod includes stimulating nerves of the foot of a patient a device andsystem according to any aspect described herein, with electrical pulsesat a frequency and amplitude able to either inhibit one or more ofbladder contractions, rectum contractions, urination, defecation, andpelvic pain of the bladder, urethra, prostate, anus or rectum, therebyobtaining the physiological response. The physiological response may beone or more of inhibition of micturition, defecation, bladdercontractions, pelvic pain of bladder, urethra, prostate, anus, orrectum, and inhibition of rectal contractions.

In one aspect, the electrical pulses range from 1 Hz to 500 Hz, such as1-50 Hz, 5-20 Hz, or 5 Hz and all subranges therebetween and overlappingtherewith. Pulsewidth may be from 0.01 to 3 ms and all subrangestherebetween and overlapping therewith. Voltage may range from 1-100 V,such as from 1-20 V or from 3-16 V, including all subranges therebetweenand overlapping therewith. Current may range from 1 mA to 100 mA. Theseranges include all subranges therein, for example 5-95 mA, 10-90 mA,15-85 mA, 20-80 mA, 25-75 mA, 30-70 mA, 35-65 mA, 40-60 mA, andsubranges therebetween and overlapping therewith.

The aforementioned parameters may be adjusted to provide from 2 T to 6T, which is suitable for, for example, inhibition of bladdercontractions; rectum contractions; for treatment of urologicalconditions, such as overactive bladder (OAB) symptoms including bladderoveractivity, urinary frequency, urinary urgency, urinary incontinence(including bedwetting), interstitial cystitis (IC), urinary retention,and pelvic pain, and for treatment of gastrointestinal conditions, suchas fecal incontinence, irritable bowel syndrome (IBS), and constipation.The pulses may be applied intermittently, for example and withoutlimitation, in two or more stimulation intervals of, for example andwithout limitation, from 0.5 to 200 seconds, with a rest period of noelectrical stimulation, able to inhibit bladder or rectal contractionsbetween stimulation intervals, or may be applied continuously. Typicallyduring the rest period, no inhibitory stimulus is applied. During therest period no electrical signal, or essentially no electrical signal isapplied. The stimulation protocol may be applied for from between 1 and360 minutes per day, for example, at least 15, 30, 45, 60, 75, 90, ormore minutes per day. The parameters identified as possible and usefulherein, for example in discussion of the device and systems above, maybe applied to the methods described herein.

As also provided by the following examples, neuromodulation by means ofadministration of pharmacological substances, in addition to or in placeof neuromodulation by electrical stimulation of the foot, can likewiseinduce either inhibitory or excitatory effect depending on the state ofthe CNS (that is, exciting or inhibiting an organ). A treatment strategythat combines foot stimulation with low-doses of drugs such astolterodine or tramadol to enhance OAB treatment efficacy lowers thepotential for unwanted side effects (Many A D et al. Combination of footstimulation and tramadol treatment reverses irritation induced bladderoveractivity in cats. J Urol 188: 2426-2432, 2012; Schwen Z et al.Combination of foot stimulation and tolterodine treatment eliminatesbladder overactivity in cats. Neurourol Urodyn 2013; in press). Theadditive effect of neuromodulation and drug therapy has also beendemonstrated clinically in patients who had incomplete responses toneuromodulation therapy alone (George E et al. Use of combinedanticholinergic medication and sacral neuromodulation in the treatmentof refractory overactive bladder. Female Pelvic Med Reconst Surg 17:97-99, 2011).

Tramadol has opioid agonist activity and can synergistically enhancefoot inhibition and produce a long-lasting post-stimulation inhibitory(Mally A D et al. Combination of foot stimulation and tramadol treatmentreverses irritation induced bladder overactivity in cats. J Urol 188:2426-2432, 2012). However, tramadol also acts as aserotonin-norepinephrine reuptake inhibitor (Grond S et al. Clinicalpharmacology of tramadol. Clin Pharmacokin 43: 879-923, 2004). Thisraises the possibility that tramadol might also influence footstimulation by enhancing serotonin and norepinephrine mechanisms. Othercompounds with similar actions on the serotonergic and noradrenergicsystems may also be utilized. For example, a low dose of duloxetine thatis not effective in inhibiting the bladder alone administered inaddition to electrical stimulation of the foot. Reducing the dose ofduloxetine could minimize the noted side-effects of the compound andthus reduce patient dropout rate. Additionally, use of receptorantagonists, such as the 5HT_(1A) antagonist, WAY100635, may be utilizedto augment duloxetine's effect on bladder overactivity, to inhibit5HT_(1A) autoreceptors in the raphe nucleus.

Accordingly, provided herein is a method of treating urological and/orgastrointestinal disorders by combining the stimulation by any aspect ofthe foot stimulation devices, systems, and/or methods described hereinwith administration of one of, or a combination of, aserotonin/norepinephrine reuptake inhibitor and/or aserotonin/norepinephrine receptor (5HT_(1A)) antagonist/blocker.Suitable serotonin/norepinephrine reuptake inhibitors include, withoutlimitation, selective serotonin reuptake inhibitors (SSRIs) such asalaproclate, citalopram, dapoxetine, escitalopram, femoxetine,fluoxetine, fluvoxamine, ifoxetine, indalpine, omiloxetine, panuramine,paroxetine, pirandamine, duloxetine, dapoxetine, sertraline, and/orzimelidine. Suitable serotonin receptor antagonists/blockers includealprenolol, AV-965, BMY-7,378, cyanopindolol, dotarizine, flopropione,GR-46,611, isodocyanopindolol, isamoltane, lecozotan, methiothepin,methysergide, MPPF, NAN-190, oxprenolol, pindobind, pindolol,propranolol, risperidone, robalzotan, SB-649,915 (which acts as both areuptake inhibitor and a receptor antagonist), SDZ-216,525, spiperone,spiramide, spiroxatrine, UH-301, WAY100135, WAY 100635, and/orxylamidine. In one aspect, the reuptake inhibitor is duloxetine and thereceptor antagonist/blocker is WAY100635. According to one aspect, acombination dosage form is provided, that includes a combination of aserotonin/norepinephrine reuptake inhibitor and aserotonin/norepinephrine receptor (5HT_(1A)) antagonist/blocker, such asany combination of a serotonin/norepinephrine reuptake inhibitor and aserotonin/norepinephrine receptor (5HT_(1A)) antagonist/blockerdescribed above. As an example, formulation of useful oral dosage formsis well within the skill of an ordinary artisan.

Previous studies investigating antidepressant effects ofserotonin-norepinephrine reuptake inhibitors have shown that theiraction on central serotonergic pathways can be amplified when combinedwith WAY100635 (Bjorvatn B et al. Venlafaxine and its interaction withWAY100635: effects on serotonergic unit activity and behavior in cats.Eur J Pharmacol 404: 121-132, 2000; Marchand F et al. Blockade ofsupraspinal 5-HT_(1A) receptors potentiates the inhibitory effect ofvenlafaxine on wind-up activity in mononeuropathic rats. Brain Res 1008:288-292, 2004). Because duloxetine's primary mechanism of action on thebladder is also believed to be through central serotonergic regulationof bladder function (Thor K B. Serotonin and norepinephrine involvementin efferent pathways to the urethral rhabdosphincter: implications fortreating stress urinary incontinence. Urol 62(4 Suppl 1): 3-9, 2003),use of a central receptor antagonist, such as WAY100635, can enhance theeffect of duloxetine on bladder overactivity.

Also provided herein is a method of treating urological and/orgastrointestinal disorders by combining stimulation using any aspect ofthe foot stimulation device, system, and method described herein incombination with administration of an anti-muscarinic compound.Anti-muscarinic compounds are anti-cholinergic compounds actingspecifically on muscarinic cholinergic receptors. The method ofstimulating the dorsal or plantar surface of the foot described hereinmay be combined with treatment, prior to, following, or concomitant withthe stimulation, with one or more of atropine, benztropine, biperiden,ipratropium, oxitropium, tiotropium, glycopyrrolate, oxybutynin,tolterodine, chlorpheniramine, diphenhydramine, dimenhydrinate,orphenadrine, trihexyphenidyl, and/or dicyclomine. In one aspect, theanti-muscarinic agent used is tolterodine, given prior to stimulation.

Also provided herein is a method of treating urological and/orgastrointestinal disorders by combining stimulation using any aspect ofthe foot stimulation device, system, and method described herein withadministration of an opioid compound. Suitable opioid compounds for usein the method include morphine, codeine, thebaine, diacetylmorphine(morphine diacetate; heroin), nicomorphine (morphine dinicotinate),dipropanoylmorphine (morphine dipropionate), desomorphine,acetylpropionylmorphine, dibenzoylmorphine, diacetyldihydromorphine,hydromorphone, hydrocodone, oxycodone, oxymorphone, ethylmorphine,buprenorphine, fentanyl, pethidine, levorphanol, methadone, tramadol,dextropropoxyphene, tapentadol, endorphins, enkephalins, dynorphins, andendomorphins. In one aspect, the opioid compound is morphine.

As used herein, any of the above-described agents used for treatingurological and/or gastrointestinal disorders is administered in anyamount deemed useful by a healthcare practitioner. In one aspect, theagent(s) is/are administered in an amount effective to reduce symptomsof overactive bladder, decrease urinary frequency, increase urineretention, reduce amplitude of mictruition contractions, reduce symptomsIC, reduce pelvic pain, reduce fecal incontinence, reduce symptoms ofIBS, and reduce constipation when used as described in combination withfoot stimulation by any device, system or method described herein.

According to one aspect, an effective dose ranges from 0.001 to 200mg/kg/day, and in certain aspects less than 100 mg/kg/day, including anyincrement or range therebetween, including 0.1 mg/kg/day, 0.5 mg/kg/day,1 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 25 mg/kg/day, 50mg/kg/day, 75 mg/kg/day, 100 mg/kg/day 125 mg/kg/day, 150 mg/kg/day, 175mg/kg/day, and 200 mg/kg/day. However, for each compound describedherein, an effective dose or dose range is expected to vary from that ofother compounds described herein for any number of reasons, includingthe molecular weight of the compound, bioavailability in the dosageform, route of administration, specific activity (e.g., EC₅₀), etc. Inany case, the effective range (e.g., the therapeutic window) between theminimally-effective dose, and maximum tolerable dose in a subject can bedetermined empirically by a person of skill in the art, with end pointsbeing determinable by in vitro and in vivo assays, and/or are acceptablein the pharmaceutical and medical arts for obtaining such informationregarding agents, such as anti-muscarinic compounds, serotonin and/ornorepinephrine reuptake inhibitors, serotonin and/or norepinephrinereceptor antagonists/blockers, and opioids. Different concentrations ofthe agents described herein are expected to achieve similar results. Thecompounds can be administered orally one or more times daily, forexample two to four times daily, once every two, three, four, five ormore days, weekly, monthly, etc., including increments therebetween. Incertain delivery methods, it is possible to deliver the drugcontinuously, or substantially continuously as in the case of, forexample, intravenous or transdermal delivery routes. A person ofordinary skill in the pharmaceutical and medical arts will appreciatethat it will be a matter of design choice and/or optimization toidentify a suitable dosage regimen for achieving the purpose of thepresent method(s).

The compounds described herein may be administered in any manner that iseffective to reduce symptoms of overactive bladder, decrease urinaryfrequency, increase urine retention, reduce amplitude of mictruitioncontractions, reduce symptoms IC, reduce pelvic pain, reduce fecalincontinence, reduce symptoms of IBS, and reduce constipation. Examplesof delivery routes include, without limitation: topical, for example,epicutaneous, inhalational, enema, ocular, otic and intranasal delivery;enteral, for example, orally, by gastric feeding tube or swallowing, andrectally; and parenteral, such as, intravenous, intraarterial,intramuscular, intracardiac, subcutaneous, intraosseous, intradermal,intrathecal, intraperitoneal, transdermal, iontophoretic, transmucosal,epidural and intravitreal, with oral or inravenous approaches beingpreferred.

Therapeutic/pharmaceutical compositions are prepared in accordance withacceptable pharmaceutical procedures, such as described in Remington:The Science and Practice of Pharmacy, 21st edition, ed. Paul Beringer etal., Lippincott, Williams & Wilkins, Baltimore, Md. Easton, Pa. (2005)(see, e.g., Chapters 37, 39, 41, 42 and 45 for examples of powder,liquid, parenteral, intravenous and oral solid formulations and methodsof making such formulations).

Any of the compounds described herein may be compounded or otherwisemanufactured into a suitable composition for use, such as apharmaceutical dosage form or drug product in which the compound is anactive ingredient. According to one example, the drug product describedherein is an oral tablet, capsule, caplet, liquid-filled or gel-filledcapsule, etc. Compositions may comprise a pharmaceutically acceptablecarrier, or excipient. An excipient is an inactive substance used as acarrier for the active ingredients of a medication. Although “inactive,”excipients may facilitate and aid in increasing the delivery, stabilityor bioavailability of an active ingredient in a drug product.Non-limiting examples of useful excipients include: antiadherents,binders, rheology modifiers, coatings, disintegrants, emulsifiers, oils,buffers, salts, acids, bases, fillers, diluents, solvents, flavors,colorants, glidants, lubricants, preservatives, antioxidants, sorbents,vitamins, sweeteners, etc., as are available in thepharmaceutical/compounding arts.

Also provided herein is a method of manufacturing anelectrode-containing device and system as described herein. The methodcomprises forming a base shaped or adapted to the dorsal or plantarsurface of a human foot and having an anterior-posterior axis. Thematerial(s) used to form the base may be any suitable materials such as,without limitation, gels, foams, rubbers, silicon-based products,polymers, neoprene, animal hides, leathers, polyethylene, ethyl vinylacetate, polypropylene, polyimide, polyester, polyethyleneterephthalate, polyaryletheretherketone, polytetrafluoroethylene,polyethylene naphthalate, co-polymer plastics, and combinations thereof.The material is preferably substantially nonconductive. Those of skillin the art are aware of methods for forming and casting bases from theidentified materials, for example gelling, polymerizing, molding,vulcanizing, and the like.

The method further includes the steps of introducing a first electrodehaving a lead at a posterior portion of the base and introducing asecond electrode having a lead at an anterior portion of the base. Theleads of the electrodes may be provided with the electrodes prior toattachment to the base, or attached to the electrodes during or afterincorporation of (attachment of) the electrodes into the base. The firstelectrode is positioned as described above to contact skin overlayingthe hindfoot and specifically the superficial peroneal nerve, deepperoneal nerve, and/or saphenous nerve (or, if the plantar surface ofthe foot is to be stimulated, the first electrode is positioned andoriented on the base to contact skin of the hindfoot, more specificallyoverlaying the medial and lateral plantar nerves in the posterior of themedial longitudinal arch). The second electrode is positioned andoriented on the base to contact skin of the forefoot, more specificallyoverlaying the superficial peroneal nerve and branches thereof (e.g.dorsal intermediate and dorsal medial cutaneous nerves), deep peronealnerve, sural nerve, and/or saphenous nerve (or the medial and lateralplantar nerves). However, as described above, the electrodes (i.e. theirpolarity) may be reversed, such that the first electrode is locatedanteriorly and the second electrode is located posteriorly.

As described above, the electrodes and leads may be formed of anysuitable material, such as, without limitation, metals and metal foils,such as, for example and without limitation, copper, gold, silver, tin,nickel, steel, cupronickel, nickel-cobalt ferrous alloys, andcarbon-based materials. The base and electrodes are formed in a mannersuch that the second electrode at the anterior position is configured toengage at least a portion of the forefoot of a human foot and configuredsuch that it covers at least 50% of the width of the forefoot, andwherein the electrode at the posterior position is configured to engagethe skin overlaying at least a portion of the calcaneus bone and/ortalus bone of a human foot and configured such that it overlays thesuperficial peroneal nerve, deep peroneal nerve, and/or saphenous nerveon skin on the dorsal surface of the foot overlaying a portion of thecalcaneus bone and/or talus bones and/or talocrural joint.

As described in detail elsewhere herein, the base may be formed in aplurality of sizes, widths, contours, etc. In aspects, the electrodesare not replaceable and are embedded within the base. In other aspects,the electrodes are replaceable, and only electrode leads and connectionsfor electrodes are embedded within the base. In such aspects, theconnector may also be embedded within the base.

The following are non-limiting examples of the use of electricalstimulation of the foot to inhibit bladder contraction, and areexemplary only and are not intended to limit the scope of the inventionsdescribed herein in any way.

EXAMPLE 1

This study was approved by the Institutional Review Board at theUniversity of Pittsburgh. Foot stimulation was tested in eight healthyhumans without OAB (5 male and 3 female, 25-60 years old, Table 1).

TABLE 1 Volume/void during 5 h Volume/void after stimulation Volume/voidduring 24 h (Mean ± SEM) during before (mL); 36 h after stimulation No.voids in stimulation Subject No.; (Mean ± SEM) time after (Mean ± SEM)Sex; Age (mL) stimulation (mL) 1; male; 46 368 ± 63 667 ± 106; 3 in 1:50465 ± 69 2; male; 49 436 ± 25 755 ± 33; 3 in 2:50 388 ± 18 3; male; 41206 ± 26 200 ± 0; 2 in 4:45 175 ± 28 4; male; 40 406 ± 71 577 ± 15; 3 in5:00 469 ± 55 5; male 25 444 ± 26 600 ± 25; 1 30 mm 368 ± 30 into stimand 1 in :10 6; female; 48 173 ± 11 195 ± 15; 2 in 1:30 238 ± 19 7;male; 47 323 ± 54 530 ± 80; 2 in 2:10 263 ± 26 8; female; 60 538 ± 78800 ± 0; 1 in 1:35 581 ± 74The subjects were instructed to record daytime voided volumes during a3-day period without any restriction on their daily food and waterintake. They were also instructed to void in response to their usualbladder sensations and to note any void that was withheld or inducedearly due to unexpected situations. Those voiding volumes that resultedfrom unexpected situations were excluded from this study.

Foot stimulation was applied for 90 minutes in the morning (10:00 AM to11:30 AM) on the second day while the subject was sitting. During thestimulation, the subject was asked to drink 1-2 bottles of water(500-1000 mL) so that a void could occur soon after stimulation. Twoskin surface electrodes (LGMedSupply, Cherry Hill, N.J.) were attachedto the bottom of the foot. A large cathodal electrode (2 inch×3.5 inch)was placed on the front of the foot to cover as much skin area aspossible and a small anodal electrode (2 inch×2 inch) was placed betweenthe inner foot arch and the heel (similar to the arrangement shown inFIG. 6A). The electrodes were connected to a transcutaneous electricalnerve stimulator (LG-TEC ELITE, LGMedSupply, Cherry Hill, N.J.) thatprovided constant current, rectangular pulses of 5 Hz frequency and 0.2ms pulse width. The subject controlled the stimulator to determine theminimal current needed to induce a toe twitch. The stimulation intensitywas then increased to a maximal level (25-60 mA) comfortable to thesubject for the entire 90 minute stimulation, which ranged between 2-6times the minimal intensity necessary to induce a toe twitch (T).

The volume per void was averaged among the subjects over three timeperiods: 1) 24 hours prior to foot stimulation; 2) up to 5 hours afterstimulation; and 3) up to 36 hours after stimulation. The second timeperiod always included the first void after the stimulation. However, ifthe voided volumes remained elevated in the following 1-2 voids, theywere also included in the second time period (see Table 1). Therefore,the second time period was variable ranging up to 5 hours, which isindicated in the third column in Table 1. The third time period includesvoids up to 36 hours after stimulation, excluding the voids counted inthe second time period. One-way ANOVA followed by Dunnett's multiplecomparison was used to detect statistically (p<0.05) significantdifferences between voided volumes before and after stimulation.

The average volume per void was 350±22 mL during the 24 hour periodprior to foot stimulation, and this volume increased to 547±152 mL(p<0.01) for up to 5 hours after the stimulation (see FIG. 15 and Table1). The average voided volume returned to 363±21 ML within 36 hoursafter stimulation. The volume per void remained elevated for severalhours following the stimulation in 3 consecutive voids (subjects #1, #2,and #4, Table 1) or 2 consecutive voids (subjects #6, and #7, Table 1).These subjects did not void during the stimulation. However, subject #5voided 625 mL 30 minutes into the stimulation period. He again voided575 mL 10 minutes after completing the 90-minute stimulation (average600±25 mL see Table 1). Both voided volumes were much larger than themean voided volume of 444±26 mL prior to stimulation. The stimulationintensity threshold (T) to induce a toe twitch varied from 10 mA to 16mA in the 8 subjects. The intensity used for the 90 minute stimulationsession varied from 2 T to 3 T (24-36 mA) in 7 subjects. In one subject(#8), a stimulation intensity of 6 T (60 mA) was used. All subjectstolerated their stimulation without any discomfort. There was noobservable change in the toe twitch during the stimulation. There wereno immediate (i.e. local skin reaction) or long-term adverse events.

EXAMPLE 2

Experiments were performed in a total of 8 adult anesthetized cats (5female and 3 male cats between 3.1-4.4 kg). Each cat was anesthetizedwith isoflurane (2-3% in O2) during surgery and then changed toα-chloralose (65 mg/kg, supplemented as necessary) anesthesia duringdata collection. A pulse oximeter (9847V, Nonin Medical Inc., Plymouth,Minn., USA) with the sensor attached to the tongue was used to monitorheart rate and blood oxygen saturation. Catheters were inserted in theright cephalic vein and right carotid artery for intravenous infusion ofdrugs and monitoring systemic blood pressure, respectively. Airwayaccess was secured with a tracheostomy tube. Ureters were accessedthrough a midline abdominal incision and drained externally. The bladderwas then cannulated with a double lumen catheter through a small cut atthe proximal urethra to infuse saline or 0.25% AA and simultaneouslymeasure bladder pressure. The proximal urethra was tied to preventleakage. Fur was removed from the right hind foot and two self-adhesivepad electrodes (Grass FE10ND, Astro-Medical Inc., Mentor, Ohio, USA;diameter 1 cm) were attached to the skin at the bottom of the foot. Oneelectrode was at the front of the foot and the other was at the heel(Chen G et al. Post-stimulation inhibitory effect on reflex bladderactivity induced by activation of somatic afferent nerves in the foot. JUrol 187: 338-343, 2012; Tai C et al. Suppression of bladderoveractivity by activation of somatic afferent nerves in the foot. BJUInt 107: 303-309, 2011).

Stimulation Protocol and Drug Administration

Uniphasic rectangular pulses (5 Hz frequency, 0.2 ms pulsewidth) weredelivered to the surface electrodes on the foot. Stimulation intensitythreshold (T) was defined as the minimal intensity to induce a toetwitch. Foot stimulation of intensities 2-4 T was used in this studysince previous studies demonstrated that this intensity range waseffective in inhibiting reflex bladder contractions (Chen G et al.Post-stimulation inhibitory effect on reflex bladder activity induced byactivation of somatic afferent nerves in the foot. J Urol 187: 338-343,2012; Mally A D et al. Combination of foot stimulation and tramadoltreatment reverses irritation induced bladder overactivity in cats. JUrol 188: 2426-2432, 2012; Tai C et al. Suppression of bladderoveractivity by activation of somatic afferent nerves in the foot. BJUInt 107: 303-309, 2011). Initially the bladder capacity was determinedduring cystometrograms (CMGs) by slowly infusing the bladder withsaline. Multiple CMGs were performed to ensure reproducibility of thesaline control capacity.

Bladder capacity was defined as the bladder volume threshold required toinduce a micturition contraction of large amplitude (>30 cm H₂O) andlong duration (>20 seconds). Then, repeated CMGs were performed withinfusion of 0.25% AA to irritate the bladder, activate nociceptivebladder afferent C-fibers, and induce bladder overactivity. When thebladder capacity stabilized, four CMGs were performed with AA infusion(Infusion rate2 mL/min) prior to the administration of duloxetine: (1)control without stimulation, (2) during 2 T stimulation, (3) during 4 Tstimulation, and (4) control without stimulation to determine anypost-stimulation effect. The bladder was emptied at the end of each CMGand a 3-5 minute rest period was inserted between CMGs.

After the pre-drug CMGs were performed, increasing cumulative doses(0.003, 0.01, 0.03, 0.1, 0.3, 1, and 3 mg/kg, i.v.) of duloxetine(Selleck Chemicals, Houston, Tex.) were given to determine the drugeffect on bladder capacity. Ten minutes after administering each dose ofduloxetine, the four CMGs were again performed with AA infusion underdifferent conditions (control, 2 T stimulation, 4 T stimulation, andpost-stimulation control). The four repeated CMGs were completed within40-60 minutes. In 4 cats 50-70 minutes after giving the maximal dose ofduloxetine (3 mg/kg), WAY100635 (Sigma-Aldrich, St. Louis, Mo.), a5HT_(1A) antagonist, was administered (0.5 mg/kg, i.v.) to block5HT_(1A) inhibitory autoreceptors on serotonergic neurons in the raphenucleus in an attempt to enhance the serotonergic inhibitory influenceof duloxetine on bladder reflexes. Five minutes after administration ofWAY100635, we performed control CMGs without stimulation to examine thecombined effect of WAY100635 and duloxetine on bladder capacity.

Data Analysis

For each CMG, bladder capacity was normalized to the initial salinecontrol capacity in the same animal, which allowed for comparisonsbetween animals. The bladder capacities were averaged for each conditionand reported with standard error of the mean. Student T-test, one wayANOVA followed by Dunnett post-tests, or two-way ANOVA followed byBonferroni posttests was used to determine the statistical significance(p<0.05).

Results Suppression of Bladder Overactivity by Foot Stimulation

After saline control CMGs were performed, AA-induced bladder irritationsignificantly (p<0.0001) reduced bladder capacity to a mean of 42.7±7.4%(5.7±1.5 mL) of saline control capacity (11.8±1.8 mL) (FIG. 16). Footstimulation significantly (p<0.0001) inhibited bladder overactivity andincreased capacity to 66.7±6.3% at 2 T and 85.7±6.5% at 4 T of salinecontrol (Foot stimulation threshold (T) defined as the minimal intensityto induce observable toe twitch. Stimulation: 5 Hz, 0.2 ms, T=11 V).Post-stimulation AA control capacity was not different frompre-stimulation AA control demonstrating that there was nopost-stimulation effect on bladder capacity (FIG. 16). In FIG. 16, theblack bar under bladder pressure trace represents the duration ofstimulation.

Dose Dependent Effect of Duloxetine on Bladder Overactivity with andwithout Stimulation

In the absence of stimulation, duloxetine dose-dependently andsignificantly (p<0.05) increased bladder capacity during AA infusion atdoses 0.1-3 mg/kg, and completely removed AA-induced overactivity at 3mg/kg increasing bladder capacity to 109±15.5% of saline control (FIGS.17(A) and 18). In FIG. 17, the CMGs were performed in sequence from leftto right in panels A-C and from top to bottom in each figure to examinea possible interaction between duloxetine and foot stimulation. Blackbar under bladder pressure trace represents the duration of stimulation.When foot stimulation was combined with duloxetine, the stimulationsignificantly (p<0.05) increased capacity after doses ranging from 0.003mg/kg to 0.03 mg/kg but did not significantly increase capacity afterdoses between 0.1 mg/kg and 3 mg/kg (FIGS. 17 and 18). After the highestdose (3 mg/kg), 2 T and 4 T stimulation significantly (p<0.05) increasedthe bladder capacity to 129.3±23.2% and 129.2±25.8% of saline control,respectively. After 2 T and 4 T stimulation in duloxetine treatedanimals, bladder capacity returned to pre-stimulation levels indicatingan absence of a post-stimulation effect.

Combined Effect of Duloxetine and WAY100635

After the final 3 mg/kg dose of duloxetine, intravenous injection ofWAY100635 (0.5168 mg/kg), which is a dose that alone does not affectbladder capacity (20, 31, 36), significantly (p=0.008) increased bladdercapacity from a mean of 117.3±17.6% to 162.2±22.5% of saline control(FIG. 19).

EXAMPLE 3

Experiments were conducted in a total of 6 adult cats (4 female and 2male cats between 2.8-3.8 kg) under achloralose anesthesia (65 mg/kg,supplemented as necessary) after induction with isoflurane (2-3% in O₂).Heart rate and blood oxygen level were monitored with a pulse oximeter(9847 V, Nonin Medical Inc., Plymouth, Minn., USA) that was attached tothe tongue. Systemic blood pressure was monitored via a catheter in theright carotid artery. These physiological parameters were monitored toensure that the animal's vital functions remained relatively stableduring the entire experiment. Drugs or fluids were administered througha catheter in the right cephalic vein and airway access was secured witha tracheostomy tube. Ureters were accessed through a midline abdominalincision and drained externally. The bladder was cannulated through theurethra with a double lumen catheter to infuse (1-2 ml/min) saline or0.25% acetic acid (AA) via one lumen and measure bladder pressure viaanother lumen. A ligature was tied around the proximal urethra toprevent leakage. Fur was removed from the foot and two self-adhesive padelectrode (Grass FE10ND, Astro-Medical. Inc., Mentor, Ohio, USA;diameter 1 cm) were attached to the skin at the bottom of the left hindfoot. One electrode was at the front of the foot and the other was atthe heel.

Stimulation Protocol and Drug Administration

Uniphasic rectangular pulses (5 Hz frequency, 0.2 ms pulsewidth) weredelivered to the skin electrodes on the foot. Threshold (T) stimulationintensity (3-16 V), which was defined as the minimal intensity to inducean observable toe twitch, was determined by slowly increasing thestimulation intensity at the beginning of the experiment. Previousstudies indicated that foot stimulation at 2 T is required to inhibitreflex bladder contractions.13 Therefore, we chose to use intensities of2 T and 4 T to suppress bladder overactivity induced by AA irritation.The initial bladder capacity was determined during a cystometrogram(CMG) by slowly infusing the bladder with saline. Bladder capacity wasdefined as the bladder volume threshold to induce a bladder reflexcontraction of large amplitude (>30 cm H₂O) and long duration (>20seconds).

Multiple CMGs were performed to determine reproducibility of the salinecontrol capacity. Then, repeated CMGs were performed with AA infusion toirritate the bladder, activate nociceptive bladder C-fiber afferents,and induce bladder overactivity. Once the irritated bladder capacity wasstabilized, four CMGs were performed prior to drug administration: 1.control CMG without stimulation; 2. CMG during 2 T stimulation; 3. CMGduring 4 T stimulation; and 4. control CMG without stimulation todetermine any post-stimulation effect. Increasing cumulative doses oftolterodine (tolterodine L-tartrate, Tocris Bioscience, Bristol, UK)were then administered (0.003, 0.01, 0.03, 0.1, and 0.3 mg/kg, i.v.).Ten minutes after administering each dose of tolterodine, the CMGs wereperformed again under the four different conditions (control, 2 Tstimulation, 4 T stimulation, and post-stimulation control) to determinethe drug effect on bladder capacity. The bladder was emptied after eachCMG followed by a 3-5 min rest period to allow the distended detrusor torecover.

Data Analysis

For the repeated CMG recordings, bladder capacity was normalized to theinitial saline control capacity in the same animal to allow comparisonsbetween animals. Capacity measurements under the same conditions wereaveraged and reported as mean±standard error of the mean (SEM). The meanamplitude of the bladder reflex contraction was also measured duringeach CMG and normalized to the AA control CMG to determine the effect oftolterodine on detrusor contractility. Statistical significance (p<0.05)was detected by ANOVA followed by Dunnett or Bonferroni post-tests.

Results Suppression of Bladder Overactivity by Foot Stimulation

AA-induced irritation of the bladder significantly (p<0.0001) reducedbladder capacity to a mean of 23.6±7.1% (2.0±0.6 mL) of saline controlcapacity (8.0±1.1 mi.) (FIG. 20, foot stimulation: 5 Hz, 0.2 ms, T=3-16V.). Prior to tolterodine administration, foot stimulation significantly(p<0.0001) increased bladder capacity to 50.7±6.8% at 2 T and 79.0±11.6%at 4 T of saline control. After stimulation, bladder capacity returnedto the pre-stimulation level (FIG. 20), indicating that there was nopost-stimulation inhibition.

Dose Dependent Effect of Tolterodine alone on Bladder Overactivity

During AA infusion CMGs, cumulative doses of tolterodine (0.003-0.3mg/kg) increased bladder capacity dose dependently in the absence offoot stimulation (FIG. 21(A), the CMGs were performed in sequence fromleft to right in (A-C) and from top to bottom in each figure. Durationof foot stimulation is indicated by the black bar under the bladderpressure trace. Stimulation: 5 Hz, 0.2 ms, T=12 V. Infusion rate=1ml/min). However, only the largest dose of tolterodine (0.3 mg/kg)significantly (p<0.05) increased the capacity (to 65.6±15.5% of thesaline control capacity) (FIG. 22(A), stimulation: 5 Hz, 0.2 ms, T=3-16V. Amplitude of micturition contraction is normalized to AA controlprior to drug administration.).

Combined Effect of Tolterodine and Foot Stimulation on BladderOveractivity

When tolterodine was combined with foot stimulation, the totalinhibitory effect was additive. Bladder capacity was significantly(p<0.05) increased by both 2 T and 4 T foot stimulation when compared toAA control at every dosage (FIGS. 21 and 22(A)). After the 0.3 mg/kgdose of tolterodine which restored the small irritated bladder to acapacity of 65.6±115.5% of saline control, 2 T or 4 T foot stimulationsignificantly increased bladder capacity to 86.2±6.2% or 107.9±10.6%,respectively, of the saline control (FIG. 22(A)). A lower dose oftolterodine (0.1 mg/kg), which was not effective in significantlyincreasing control bladder capacity in the absence of stimulation,significantly (p<0.05) increased bladder capacity to 97.0±11.2% ofsaline control when combined with 4 T foot stimulation. Thus,combination therapy completely restored the irritated bladder to thecapacity equivalent to the saline control (see the dashed line in FIG.22(A)). After 2 T and 4 T stimulation, the bladder capacity returned tothe pre-stimulation level at every dose of tolterodine, i.e. nopost-stimulation effect was observed.

Tolterodine (0.003-0.3 mg/kg) did not alter the amplitude of bladderreflex contractions during control, 2 T or 4 T foot stimulation CMGs(FIGS. 21 and 22(B)). Foot stimulation at 4 T significantly (p<0.05)increased the contraction amplitude only at 0 mg/kg and 0.01 mg/kgtolterodine (FIG. 22(B)). The threshold pressure (5.0±1.3 cm H₂O) forinducing a micturition reflex was significantly (p<0.05) increased byfoot stimulation (7.1±0.9 cm H₂O at 2 T; 8.5±1.0 cm H₂O at 4 T) and bytolterodine treatment (8.1±1.4 cm H₂O at 0.3 mg/kg).

EXAMPLE 4

In this experiment, 20 adults with overactive bladder received footneuromodulation with a device as described herein. The experiment was athree-week trial, as shown in FIG. 23. Specifically 20 adults weremonitored for three weeks. No stimulation was applied during the firstand third weeks (FIG. 23). During the second week of the trial,participants utilized a device as described herein, with electrodeplacement on the plantar surface of the foot as shown in FIG. 23. Theacute effect of foot neuromodulation was determined during the secondweek, while the long-lasting post-stimulation effect was detected duringthe last week. During the second week, foot stimulation (5 Hz, 0.2 mspulsewidth). The participants were asked to increase the stimulationintensity to as high of a level as possible without pain/discomfort. Thestimulation was applied for three hours each day. As shown in FIG. 23,participants who showed a response to the treatment (N=16) maintained aurine diary, recording voiding frequency, incontinence frequency,urgency frequency, and episodes of nocturia (waking at night tourinate). These observations occurred for the periods illustrated inFIG. 23.

Results from this experiment are shown in FIGS. 24-26. FIG. 24 showsthat participants reported significantly (p<0.05) less voiding (panelA), lower urgency frequency (B), lower incontinence frequency (C), andfewer episodes of nocturia per night (D) following initiation of footneuromodulation. These results are provided in tabular form in FIG. 26,which further shows that stimulation resulted in larger volume (mL/void,p=0.0465), less strength per void (p=0.001), and lower severity per void(p=0.0006). When measuring incontinence severity, the scale is 0-3, with0 being no severity, 1 and 2 being a little and moderate severity, and 3being a large amount. Similarly, when measuring urgency strength, 0 isno strength, with 1 and 2 being mild and moderate strength and 3 beingsevere. FIG. 25 shows the average stimulation intensity for theparticipants during each of the days during the second week, whenstimulation was applied. As can be seen, the average intensity was above60 mA, or about 2.5 T (toe-twitch threshold), which was 26.2 mA in thecohort.

The results of this experiment show that foot neuromodulation, withsimple stimulation for only three hours per day with a device asdescribed herein, improve symptoms of overactive bladder in adults.

EXAMPLE 5

In this experiment a device, system, and method as described herein wasutilized to prevent bedwetting by foot neuromodulation, which stimulatesthe nerves in the foot during the day using skin surface electrodes tomodulate bladder reflex activity during the night. Foot neuromodulationtherapy eliminates the sleep disruptions associated with bedwettingalarms and many side effects associated with the drug treatments.

In this experiment, 20 children (mean age 11.2 years) underwent footneuromodulation with a device as described herein (see, e.g., FIG. 13).The experiment was a six-week trial. Specifically, 20 children weremonitored for six weeks. No stimulation was applied during weeks 1, 2,5, and 6. During weeks 3 and 4 of the trial, participants utilized adevice as described herein, with electrode placement on the plantarsurface of the foot as shown in. FIG. 27. The acute effect of footneuromodulation was determined during the 3rd and 4th weeks, while thelong-lasting post-stimulation effect was detected during the last 2weeks. During these two weeks, foot stimulation (5 Hz, 0.2 ms pulsewidth). Average intensity of the stimulation is shown in FIG. 27.Participants were asked to increase the intensity to as high of a levelas possible without discomfort. Stimulation was applied for one houreach day, at night before sleep. Participants were asked to increase theintensity (mA) of the stimulation to as high of a level as possiblewithout causing discomfort, and were asked to record a night-timevoiding log specifying the number of bedwetting nights the 6-weekperiod.

Results from the experiment are shown in. FIGS. 27 and 28. FIG. 27 showsaverage intensity (mA) for children during weeks 3 and 4. FIG. 28 showsthe number of bedwetting nights in the initial two weeks (Control),during the two weeks when stimulation was applied (Stim), and duringweeks 5 and 6, when no stimulation was applied (After-stim). As thegraph shows, children who responded to the treatment (N=14) exhibitedfewer bedwetting nights during stimulation (p<0.01) and afterstimulation (p<0.01), suggesting a long-term effect of footneuromodulation.

The results of the experiment show that foot neuromodulation is thefirst treatment that is effective for treatment of bedwetting. Thistreatment is accomplished without disrupting the sleep of the childrenand their parents, thereby reducing the stress for the family. Mostimportantly, it is safe without any side effects, and thus couldcompletely change the current clinical practice in the treatment ofbedwetting.

EXAMPLE 6

The subjects are instructed to record daytime voided volumes during a3-day period without any restriction on their daily food and waterintake. They are also instructed to void in response to their usualbladder sensations and to note any void that was withheld or inducedearly due to unexpected situations. Those voiding volumes that resultedfrom unexpected situations are excluded from the study.

Foot stimulation is applied for 90 minutes in the morning (10:00 AM to11:30 AM) on the second day while the subject is sitting. During thestimulation, the subject is asked to drink 1-2 bottles of water(500-1000 mL) so that a void could occur soon after stimulation. Twoskin surface electrodes (LGMedSupply, Cherry Hill, N.J.) are attached tothe top surface of the foot. A large cathodal electrode (2 inch×3.5inch) is placed on the front of the foot to cover as much skin area aspossible and a small anodal electrode (2 inch×2 inch) is placed betweenthe first electrode and the talocrural joint (ankle) (similar to thearrangement of electrodes shown in FIG. 5). The electrodes are connectedto a transcutaneous electrical nerve stimulator (LG-TEC ELITE,LGMedSupply, Cherry Hill, N.J.) that provides constant current,rectangular pulses of 5 Hz frequency and 0.2 ms pulse width. The subjectcontrols the stimulator to determine the minimal current needed toinduce a toe twitch. The stimulation intensity is then increased to amaximal level (25-60 mA) comfortable to the subject for the entire 90minute stimulation, which ranges between 2-6 times the minimal intensitynecessary to induce a toe twitch (T).

The volume per void is averaged among the subjects over three timeperiods: 1) 24 hours prior to foot stimulation; 2) up to 5 hours afterstimulation; and 3) up to 36 hours after stimulation. The second timeperiod always includes the first void after the stimulation. However, ifthe voided volumes remain elevated in the following 1-2 voids, they arealso included in the second time period. Therefore, the second timeperiod is variable ranging up to 5 hours. The third time period includesvoids up to 36 hours after stimulation, excluding the voids counted inthe second time period. One-way ANOVA followed by Dunnett's multiplecomparison is used to detect statistically (p<0.05) significantdifferences between voided volumes before and after stimulation.

EXAMPLE 7

The subjects are instructed to record daytime voided volumes during a3-day period without any restriction on their daily food and waterintake. They are also instructed to void in response to their usualbladder sensations and to note any void that was withheld or inducedearly due to unexpected situations. Those voiding volumes that resultedfrom unexpected situations are excluded from the study.

Foot stimulation is applied for 90 minutes in the morning (10:00 AM to11:30 AM) on the second day while the subject is sitting. During thestimulation, the subject is asked to drink 1-2 bottles of water(500-1000 mL) so that a void could occur soon after stimulation. Twoskin surface electrodes (LGMedSupply, Cherry Hill, N.J.) are attached tothe bottom surface of the foot. A large cathodal electrode (2 inch×3.5inch) is placed on the front of the foot to cover as much skin area aspossible and a small anodal electrode (2 inch×2 inch) is placed betweenthe first electrode and the talocrural joint (ankle) (similar to thearrangement of electrodes shown in FIG. 6). The electrodes are connectedto a transcutaneous electrical nerve stimulator (LG-TEC ELITE,LGMedSupply, Cherry Hill, N.J.) that provides constant current,rectangular pulses of 5 Hz frequency and 0.2 ms pulse width. The subjectcontrols the stimulator to determine the minimal current needed toinduce a toe twitch. The stimulation intensity is then increased to amaximal level (25-60 mA) comfortable to the subject for the entire 90minute stimulation, which ranges between 2-6 times the minimal intensitynecessary to induce a toe twitch (T).

The volume per void is averaged among the subjects over three timeperiods: 1) 24 hours prior to foot stimulation; 2) up to 5 hours afterstimulation; and 3) up to 36 hours after stimulation. The second timeperiod always includes the first void after the stimulation. However, ifthe voided volumes remain elevated in the following 1-2 voids, they arealso included in the second time period. Therefore, the second timeperiod is variable ranging up to 5 hours. The third time period includesvoids up to 36 hours after stimulation, excluding the voids counted inthe second time period. One-way ANOVA followed by Dunnett's multiplecomparison is used to detect statistically (p<0.05) significantdifferences between voided volumes before and after stimulation.

EXAMPLE 8

Experiments are performed in adult anesthetized cats. Each cat isanesthetized with isoflurane (2-3% in O2) during surgery and thenchanged to α-chloralose (65 mg/kg, supplemented as necessary) anesthesiaduring data collection. A pulse oximeter (9847V, Nonin Medical Inc.,Plymouth, Minn., USA) with the sensor attached to the tongue is used tomonitor heart rate and blood oxygen saturation. Catheters are insertedin the right cephalic vein and right carotid artery for intravenousinfusion of drugs and monitoring systemic blood pressure, respectively.Airway access is secured with a tracheostomy tube. Ureters are accessedthrough a midline abdominal incision and drained externally. The bladderis then cannulated with a double lumen catheter through a small cut atthe proximal urethra to infuse saline or 0.25% AA and simultaneouslymeasure bladder pressure. The proximal urethra is tied to preventleakage. Fur is removed from the right hind foot and two self-adhesivepad electrodes (Grass FE10ND, Astro-Medical Inc., Mentor, Ohio, USA;diameter 1 cm) are attached to the skin at the top of the foot. Oneelectrode is at the front of the foot and the other is between the firstelectrode and the talocrural joint.

Stimulation Protocol and Drug Administration

Uniphasic rectangular pulses (5 Hz frequency, 0.2 ms pulsewidth) aredelivered to the surface electrodes on the foot. Stimulation intensitythreshold (T) is defined as the minimal intensity to induce a toetwitch. Foot stimulation of intensities 2-4 T are used in this studysince previous studies demonstrated that this intensity range waseffective in inhibiting reflex bladder contractions. Initially thebladder capacity is determined during cystometrograms (CMGs) by slowlyinfusing the bladder with saline. Multiple CMGs are performed to ensurereproducibility of the saline control capacity.

Bladder capacity is defined as the bladder volume threshold required toinduce a micturition contraction of large amplitude (>30 cm H₂O) andlong duration (>20 seconds). Then, repeated CMGs are performed withinfusion of 0.25% AA to irritate the bladder, activate nociceptivebladder afferent C-fibers, and induce bladder overactivity. When thebladder capacity stabilizes, four CMGs are performed with AA infusionprior to the administration of duloxetine; (1) control withoutstimulation; (2) during 2 T stimulation; (3) during 4 T stimulation; and(4) control without stimulation to determine any post-stimulationeffect. The bladder is emptied at the end of each CMG and a 3-5 minuterest period is inserted between CMGs.

After the pre-drug CMGs are performed, increasing cumulative doses(0.003, 0.01, 0.03, 0.1, 0.3, 1, and 3 mg/kg, i.v.) of duloxetine(Selleck Chemicals, Houston, Tex.) are given to determine the drugeffect on bladder capacity. Ten minutes after administering each dose ofduloxetine, the four CMGs are again performed with AA infusion underdifferent conditions (control, 2 T stimulation, 4 T stimulation, andpost-stimulation control). The four repeated CMGs are completed within40-60 minutes.

EXAMPLE 9

Experiments are performed in adult anesthetized cats. Each cat isanesthetized with isoflurane (2-3% in O2) during surgery and thenchanged to α-chloralose (65 mg/kg, supplemented as necessary) anesthesiaduring data collection. A pulse oximeter (9847V, Nonin Medical Inc.,Plymouth, Minn., USA) with the sensor attached to the tongue is used tomonitor heart rate and blood oxygen saturation. Catheters are insertedin the right cephalic vein and right carotid artery for intravenousinfusion of drugs and monitoring systemic blood pressure, respectively.Airway access is secured with a tracheostomy tube. Ureters are accessedthrough a midline abdominal incision and drained externally. The bladderis then cannulated with a double lumen catheter through a small cut atthe proximal urethra to infuse saline or 0.25% AA and simultaneouslymeasure bladder pressure. The proximal urethra is tied to preventleakage. Two self-adhesive pad electrodes (Grass FE10ND, Astro-MedicalInc., Mentor, Ohio, USA; diameter 1 cm) are attached to the skin at thebottom of the foot. One electrode is at the front of the foot and theother is between the first electrode and the talocrural joint.

Stimulation Protocol and Drug Administration

Uniphasic rectangular pulses (5 Hz frequency, 0.2 ms pulsewidth) aredelivered to the surface electrodes on the foot. Stimulation intensitythreshold (T) is defined as the minimal intensity to induce a toetwitch. Foot stimulation of intensities 2-4 T are used in this studysince previous studies demonstrated that this intensity range waseffective in inhibiting reflex bladder contractions. Initially thebladder capacity is determined during cystometrograms (CMGs) by slowlyinfusing the bladder with saline. Multiple CMGs are performed to ensurereproducibility of the saline control capacity.

Bladder capacity is defined as the bladder volume threshold required toinduce a micturition contraction of large amplitude (>30 cm H₂O) andlong duration (>20 seconds). Then, repeated CMGs are performed withinfusion of 0.25% AA to irritate the bladder, activate nociceptivebladder afferent C-fibers, and induce bladder overactivity. When thebladder capacity stabilizes, four CMGs are performed with AA infusionprior to the administration of duloxetine; (1) control withoutstimulation; (2) during 2 T stimulation; (3) during 4 T stimulation; and(4) control without stimulation to determine any post-stimulationeffect. The bladder is emptied at the end of each CMG and a 3-5 minuterest period is inserted between CMGs.

After the pre-drug CMGs are performed, increasing cumulative doses(0.003, 0.01, 0.03, 0.1, 0.3, 1, and 3 mg/kg, i.v.) of duloxetine(Selleck Chemicals, Houston, Tex.) are given to determine the drugeffect on bladder capacity. Ten minutes after administering each dose ofduloxetine, the four CMGs are again performed with AA infusion underdifferent conditions (control, 2 T stimulation, 4 T stimulation, andpost-stimulation control). The four repeated CMGs are completed within40-60 minutes.

Data Analysis

For each CMG, bladder capacity is normalized to the initial salinecontrol capacity in the same animal, which allows for comparisonsbetween animals. The bladder capacities are averaged for each conditionand reported with standard error of the mean. Student T-test, one wayANOVA followed by Dunnett post-tests, or two-way ANOVA followed byBonferroni posttests are used to determine the statistical significance(p<0.05).

EXAMPLE 10

Experiments are conducted in adult cats under alpha-chloraloseanesthesia (65 mg/kg, supplemented as necessary) after induction withisoflurane (2-3% in O₂). Heart rate and blood oxygen level are monitoredwith a pulse oximeter (9847 V, Nonin. Medical Inc., Plymouth, Minn.,USA) that is attached to the tongue. Systemic blood pressure ismonitored via a catheter in the right carotid artery. Thesephysiological parameters are monitored to ensure that the animal's vitalfunctions remain relatively stable during the entire experiment. Drugsor fluids are administered through a catheter in the right cephalic veinand airway access is secured with a tracheostomy tube. Ureters areaccessed through a midline abdominal incision and drained externally.The bladder is cannulated through the urethra with a double lumencatheter to infuse (1-2 ml/min) saline or 0.25% AA via one lumen andmeasure bladder pressure via another lumen. A ligature is tied aroundthe proximal urethra to prevent leakage. Fur is removed from the footand two self-adhesive pad electrode (Grass FE10ND, Astro-Medical Inc.,Mentor, Ohio, USA; diameter 1 cm) are attached to the skin at the top ofthe left hind foot. One electrode was at the front of the foot and theother was at the hindfoot, near the talocrural (ankle) joint.

Stimulation Protocol and Drug Administration

Uniphasic rectangular pulses (5 Hz frequency, 0.2 ms pulsewidth) aredelivered to the skin electrodes on the foot. Threshold (T) stimulationintensity (3-16 V), which is defined as the minimal intensity to inducean observable toe twitch, is determined by slowly increasing thestimulation intensity at the beginning of the experiment. Previousstudies indicated that foot stimulation at 2 T is required to inhibitreflex bladder contractions. Therefore, intensities of 2 T and 4 T areused to suppress bladder overactivity induced by AA irritation. Theinitial bladder capacity is determined during a cystometrogram (CMG) byslowly infusing the bladder with saline. Bladder capacity is defined asthe bladder volume threshold to induce a bladder reflex contraction oflarge amplitude (>30 cm H₂O) and long duration (>20 seconds).

Multiple CMGs are performed to determine reproducibility of the salinecontrol capacity. Then, repeated CMGs are performed with AA infusion toirritate the bladder, activate nociceptive bladder C-fiber afferents,and induce bladder overactivity. Once the irritated bladder capacity isstabilized, four CMGs are performed prior to drug administration: 1.control CMG without stimulation; 2. CMG during 2 T stimulation; 3. CMGduring 4 T stimulation; and 4. control CMG without stimulation todetermine any post-stimulation effect. Increasing cumulative doses oftolterodine (tolterodine L-tartrate, Tocris Bioscience, Bristol, UK) arethen administered (0.003, 0.01, 0.03, 0.1, and 0.3 mg/kg, i.v.). Tenminutes after administering each dose of tolterodine, the CMGs areperformed again under the four different conditions (control, 2 Tstimulation, 4 T stimulation, and post-stimulation control) to determinethe drug effect on bladder capacity. The bladder is emptied after eachCMG followed by a 3-5 min rest period to allow the distended detrusor torecover.

Data Analysis

For the repeated CMG recordings, bladder capacity is normalized to theinitial saline control capacity in the same animal to allow comparisonsbetween animals. Capacity measurements under the same conditions areaveraged and reported as mean 21, standard error of the mean (SEM). Themean amplitude of the bladder reflex contraction is also measured duringeach CMG and normalized to the AA control CMG to determine the effect oftolterodine on detrusor contractility. Statistical significance (p<0.05)is detected by ANOVA followed by Dunnett or Bonferroni post-tests.

EXAMPLE 11

Experiments are conducted in adult cats under achloralose anesthesia (65mg/kg, supplemented as necessary) after induction with isoflurane (2-3%in O₂). Heart rate and blood oxygen level are monitored with a pulseoximeter (9847 V, Nonin Medical Inc., Plymouth, Minn., USA) that isattached to the tongue. Systemic blood pressure is monitored via acatheter in the right carotid artery. These physiological parameters aremonitored to ensure that the animal's vital functions remain relativelystable during the entire experiment. Drugs or fluids are administeredthrough a catheter in the right cephalic vein and airway access issecured with a tracheostomy tube. Ureters are accessed through a midlineabdominal incision and drained externally. The bladder is cannulatedthrough the urethra with a double lumen catheter to infuse (1-2 ml/min)saline or 0.25% AA via one lumen and measure bladder pressure viaanother lumen. A ligature is tied around the proximal urethra to preventleakage. Two self-adhesive pad electrode (Grass FE10ND, Astro-MedicalInc., Mentor, Ohio, USA; diameter 1 cm) are attached to the skin at thebottom of the left hind foot. One electrode was at the front of the footand the other was at the hindfoot, near the talocrural (ankle) joint.

Stimulation Protocol and Drug Administration

Uniphasic rectangular pulses (5 Hz frequency, 0.2 ms pulsewidth) aredelivered to the skin electrodes on the foot. Threshold (T) stimulationintensity (3-16 V), which is defined as the minimal intensity to inducean observable toe twitch, is determined by slowly increasing thestimulation intensity at the beginning of the experiment. Previousstudies indicated that foot stimulation at 2 T is required to inhibitreflex bladder contractions. Therefore, intensities of 2 T and 4 T areused to suppress bladder overactivity induced by AA irritation. Theinitial bladder capacity is determined during a cystometrogram (CMG) byslowly infusing the bladder with saline. Bladder capacity is defined asthe bladder volume threshold to induce a bladder reflex contraction oflarge amplitude (>30 cm H₂O) and long duration (>20 seconds).

Multiple CMGs are performed to determine reproducibility of the salinecontrol capacity. Then, repeated CMGs are performed with AA infusion toirritate the bladder, activate nociceptive bladder C-fiber afferents,and induce bladder overactivity. Once the irritated bladder capacity isstabilized, four CMGs are performed prior to drug administration: 1.control CMG without stimulation; 2. CMG during 2 T stimulation; 3. CMGduring 4 T stimulation; and 4. control CMG without stimulation todetermine any post-stimulation effect. Increasing cumulative doses oftolterodine (tolterodine L-tartrate, Tocris Bioscience, Bristol, UK) arethen administered (0.003, 0.01, 0.03, 0.1, and 0.3 mg/kg, i.v.). Tenminutes after administering each dose of tolterodine, the CMGs areperformed again under the four different conditions (control, 2 Tstimulation, 4 T stimulation, and post-stimulation control) to determinethe drug effect on bladder capacity. The bladder is emptied after eachCMG followed by a 3-5 min rest period to allow the distended detrusor torecover.

Data Analysis

For the repeated CMG recordings, bladder capacity is normalized to theinitial saline control capacity in the same animal to allow comparisonsbetween animals. Capacity measurements under the same conditions areaveraged and reported as mean standard error of the mean (SEM). The meanamplitude of the bladder reflex contraction is also measured during eachCMG and normalized to the AA control CMG to determine the effect oftolterodine on detrusor contractility. Statistical significance (p<0.05)is detected by ANOVA followed by Dunnett or Bonferroni post-tests.

The invention can be further characterized in the following numberedclauses.

Clause 1: An electrode-containing device comprising: a base adapted tocover a portion of a plantar surface of a human foot including a portionof the forefoot overlaying a plurality of branches of the medial orlateral plantar nerves and a portion of the hindfoot overlaying themedial and lateral plantar nerves; a first electrode attached to thebase at a position adapted to the hindfoot to contact skin overlayingthe medial and lateral plantar nerves; a second electrode attached tothe base at a position adapted to the forefoot to contact skinoverlaying a plurality of branches of the medial or lateral plantarnerves in the forefoot; and a first and second electrical lead attachedto the first and second electrodes, respectively.

Clause 2: The electrode-containing device of clause 1, in which thefirst electrode is a cathode and the second electrode is an anode.

Clause 3: The electrode-containing device of clause 1, in which thefirst electrode is an anode and the second electrode is a cathode.

Clause 4: The electrode-containing device of any of clauses 1-3, inwhich the second electrode overlays at least 50% of the width of thesole at the forefoot.

Clause 5: The electrode-containing device of any of clauses 1-4, inwhich the second electrode overlays at least a portion of themetatarsophalangeal joint.

Clause 6: The electrode-containing device of any of clauses 1-5, inwhich the first electrode overlays at least a portion of the calcaneusbone.

Clause 7: The electrode-containing device of any of clauses 1-6, inwhich the second electrode overlays a predominance of branches of themedial and lateral plantar nerves in the forefoot.

Clause 8: The electrode-containing device of any of clauses 1-7, whereinthe base has a perimeter having the shape of a sole of a foot, andoptionally is an orthotic insert.

Clause 9: The electrode-containing device of any of clauses 1-8, whereinthe base is a thin polymeric film having an adhesive on a sidecomprising the electrodes and facing the foot.

Clause 10: The electrode-containing device of any of clauses 1-9,further comprising one or more connectors for an external pulsegenerator attached to the leads.

Clause 11: The electrode-containing device of any of clauses 1-10,further comprising an adhesive on a surface of the base and/orelectrodes for removably securing the device to a patient's foot.

Clause 12: The electrode-containing device of any of clauses 1-11,wherein the base is shaped substantially like a plantar surface or soleof a human foot.

Clause 13: An electrical nerve stimulation system comprising: anelectrode-containing device of any of clauses 1-12; a pulse generatorexternal to the electrode-containing device and connected to the leads,configured to generate pulses of pulsewidth 0.01-3 ms between 1-100 Vand 1-100 mA, at frequency 1-50 Hz.

Clause 14: The system of clause 13, in which the pulse generatorcomprises an adjustment mechanism for adjusting one or more parametersof the pulses.

Clause 15: The system of clause 13 or 14, in which the adjustmentmechanism comprise a wireless receiver in wireless communication with awireless controller.

Clause 16: The system of any of clauses 13-15, wherein the pulsegenerator produces monophasic, rectangular pulses or biphasic pulses.

Clause 17: The system of any of clauses 13-16, wherein the pulsegenerator provides pulses having a pulsewidth of 0.2 ms at 5 Hz, andwherein the intensity of the pulses is from 2-6 times a toe twitchthreshold of a patient.

Clause 18: The system of any of clauses 13-17, wherein the pulsegenerator provides a fixed output of pulses of pulsewidth 0.01-3 msbetween 1-100 V and 1-80 mA, at frequency 1-50 Hz.

Clause 19: A method of treating urological or gastrointestinal disorderscomprising: applying an electrode-containing device of any of clauses1-12 to a foot of a patient in need of such treatment, wherein theelectrode-containing device is attached to a pulse generator external tothe electrode-containing device comprising a connector for connectingthe pulse generator to the device; and stimulating the patient's footwith the device with pulses of pulsewidth 0.01-3 ms between 1-100 V and1-100 mA, at frequency 1-50 Hz, thereby stimulating the lateral andmedial plantar nerves of the patient.

Clause 20: The method of clause 19, in which the urological orgastrointestinal disorder is one or more of: overactive bladder (OAB)symptoms including bladder overactivity, urinary frequency, urinaryurgency, urinary incontinence; interstitial cystitis (IC); urinaryretention; pelvic pain; fecal incontinence; irritable bowel syndrome(IBS); and constipation.

Clause 21: The method of clause 19 or 20, in which the urological orgastrointestinal disorder is urinary incontinence.

Clause 22: The method of any of clauses 19-21, in which the urinaryincontinence is bedwetting, and, optionally, with pulses of a frequencyof 5 Hz, 0.2 ms pulsewidth, and/or from greater than 0 mA to 80 mA.

Clause 23: The method of any of clauses 19-22, wherein the pulsegenerator provides pulses having a pulsewidth of 0.2 ms at 5 Hz, andwherein the intensity of the pulses is from 2-6 times a toe twitchthreshold of a patient.

Clause 24: The method of any of clauses 19-23, wherein the patient'sfoot is stimulated for from 1 to 360 minutes.

Clause 25: The method of any of clauses 19-24, wherein the patient'sfoot is stimulated for at least 30 minutes.

Clause 26: The method of any of clauses 19-25, wherein the patient'sfoot is stimulated for at least 180 minutes.

Clause 27: The method of any of clauses 19-26, further comprisingadministering an anti-muscarinic compound to the patient.

Clause 28: The method of clause 27, wherein the anti-muscarinic compoundis selected from the group consisting of atropine, benztropine,biperiden, ipratropium, oxitropium, tiotropium, glycopyrrolate,oxybutynin, tolterodine, chlorpheniramine, diphenhydramine,dimenhydrinate, orphenadrine, trihexyphenidyl, and dicyclomine.

Clause 29: The method of clause 27 or 28, wherein the anti-muscariniccompound is tolterodine.

Clause 30: The method of any of clauses 27-29, wherein theanti-muscarinic compound is administered at between 0.003 and 1 mg/kg.

Clause 31: The method of any of clauses 27-30, wherein theanti-muscarinic compound is administered orally or parenterally.

Clause 32: The method of any of clauses 19-31, further comprisingadministering to a patient in need thereof a serotonin reuptakeinhibitor and/or a serotonin receptor antagonist.

Clause 33: The method of clause 32, wherein the serotonin reuptakeinhibitor is selected from the group consisting of alaproclate,citalopram, dapoxetine, escitalopram, femoxetine, fluoxetine,fluvoxamine, ifoxetine, indalpine, omiloxetine, panuramine, paroxetine,pirandamine, duloxetine, dapoxetine, sertraline, and zimelidine and theserotonin receptor antagonist is selected from the group consisting ofalprenolol, AV-965, BMY-7,378, cyanopindolol, dotarizine, flopropione,GR-46,611, isodocyanopindolol, isamoltane, lecozotan, methiothepin.,methysergide, MPPF, NAN-190, oxprenolol, pindobind, pindolol,propranolol, risperidone, robalzotan, SB-649,915 (which acts as both areuptake inhibitor and a receptor antagonist), SDZ-216,525, spiperone,spiramide, spiroxatrine, UH-301, WAY100135, WAY 100635, and xylamidine.

Clause 34: The method of clause 32 or 33, wherein the serotonin reuptakeinhibitor is duloxetine.

Clause 35: The method of any of clauses 32-34, wherein the serotoninreceptor antagonist is WAY100635.

Clause 36: The method of any of clauses 32-35, comprising administeringboth a serotonin reuptake inhibitor and a serotonin receptor antagonist.

Clause 37: The method of any of clauses 32-36, in which the serotoninreuptake inhibitor is duloxetine and the serotonin receptor antagonistis WAY100635.

Clause 38: The method of any of clauses 32-37, wherein the serotoninreuptake inhibitor is administered at between 0.003 and 5 mg/kg and theserotonin receptor antagonist is administered at between 0.1 and 1mg/kg.

Clause 39: The method of any of clauses 32-38, wherein the serotoninreuptake inhibitor or the serotonin receptor antagonist are administeredorally of parenterally.

Clause 40: The method of any of clauses 19-39, further comprisingadministering an opioid drug to the patient.

Clause 41: The method of clause 40, wherein the opioid drug is selectedfrom the group consisting of morphine, codeine, thebaine,diacetylmorphine (morphine diacetate; heroin), nicomorphine (morphinedinicotinate), dipropanoylmorphine (morphine dipropionate),desomorphine, acetylpropionylmorphine, dibenzoylmorphine,diacetyldihydromorphine, hydromorphone, hydrocodone, oxycodone,oxymorphone, ethylmorphine, buprenorphine, fentanyl, pethidine,levorphanol, methadone, tramadol, dextropropoxyphene, tapentadol,endorphins, enkephalins, dynorphins, and endomorphins.

Clause 42: The method of clause 40 or 41, wherein the opioid drug istramadol.

Clause 43: The method of any of clauses 40-42, wherein the opioid drugis administered at between 0.003 and 1 mg/kg.

Clause 44: The method of any of clauses 40-43, wherein the opioid drugis administered orally or parenterally.

Clause 45: A method of manufacturing an electrode-containing devicecomprising: forming a base adapted to cover a portion of a bottomsurface of a human foot including a portion of the forefoot overlaying aplurality of branches of the medial or lateral plantar nerves and aportion of the hindfoot overlaying the medial and lateral plantarnerves; attaching a first electrode to the base at a position in thebase adapted to contact skin overlaying the medial and lateral plantarnerves; attaching a second electrode to the base at a position in thebase adapted to contact skin overlaying a plurality of branches of themedial or lateral plantar nerves in the forefoot; and attachingelectrode leads for the first and second electrodes to the base.

Clause 46: The method of clause 45, wherein the second electrode isadapted to engage skin of the sole of the foot over at least 50% of thewidth of the forefoot.

Clause 47: The method of clause 45 or 46, in which a plurality of thedevices are manufactured to accommodate a plurality of standardized footsizes.

Clause 48: The method of any of clauses 45-47, in which the electrodesare embedded within the base.

Clause 49: The method of any of clauses 45-48, in which the base isconfigured to have a perimeter having the shape of a sole of a foot, andoptionally is an orthotic insert.

Clause 50: The method of any of clauses 45-49, wherein electrode leadsare embedded within the base.

Clause 51. An electrode-containing device comprising: a base adapted tocover a portion of a dorsal surface of a human foot including a portionof the forefoot overlaying a plurality of branches of the dorsalintermediate and medial cutaneous nerves, deep peroneal nerve, suralnerve, and/or saphenous nerve, and a portion of the hindfoot overlayingthe superficial peroneal nerve, deep peroneal nerve, and/or saphenousnerve; a first electrode attached to the base at a position adapted to adorsal portion of the hindfoot to contact skin overlaying thesuperficial peroneal nerve, deep peroneal nerve, and/or saphenous nerve;a second electrode attached to the base at a position adapted to adorsal portion of the forefoot to contact skin overlaying a plurality ofbranches of the dorsal intermediate and medial cutaneous nerves, deepperoneal nerve, sural nerve, and/or saphenous nerve in the forefoot; anda first and second electrical lead attached to the first and secondelectrodes, respectively.

Clause 52: The electrode-containing device of clause 51, in which thefirst electrode is a cathode and the second electrode is an anode.

Clause 53: The electrode-containing device of clause 51, in which thefirst electrode is an anode and the second electrode is a cathode.

Clause 54: The electrode-containing device of any of clauses 51-53, inwhich the second electrode overlays at least 50% of the width of thefoot at the forefoot.

Clause 55: The electrode-containing device of any of clauses 51-54, inwhich the second electrode overlays at least a portion of themetatarsophalangeal joint.

Clause 56: The electrode-containing device of any of clauses 51-55, inwhich the first electrode overlays at least a portion of the calcaneusbone.

Clause 57: The electrode-containing device of any of clauses 51-56, inwhich the second electrode overlays a predominance of branches of thedorsal intermediate and medial cutaneous nerves, deep peroneal nerve,sural nerve, and/or saphenous nerve in the forefoot.

Clause 58: The electrode-containing device of any of clauses 51-57,wherein the base has a perimeter having the shape of the dorsal area ofa foot from the proximal phalanges to the talocrural joint.

Clause 59: The electrode-containing device of any of clauses 51-58,wherein the base is a thin polymeric film having an adhesive on a sidecomprising the electrodes and facing the foot.

Clause: 60: The electrode-containing device of any of clauses 51-59,further comprising one or more connectors for an external pulsegenerator attached to the leads.

Clause 61: The electrode-containing device of any of clauses 51-60further comprising an adhesive on a surface of the base and/orelectrodes for removably securing the device to a patient's foot.

Clause 62: The electrode-containing device of any of clauses 51-61,wherein the base is shaped substantially to interact with the dorsalsurface of a human foot.

Clause 63: An electrical nerve stimulation system comprising: anelectrode-containing device of any of clauses 51-62; a pulse generatorexternal to the electrode-containing device and connected to the leads,configured to generate pulses of between 1-1.00 V and 1-100 mA, having apulsewidth of 0.01-3 ms, at frequency 1-50 Hz.

Clause 64: The system of clause 63, in which the pulse generatorcomprises an adjustment mechanism for adjusting one or more parametersof the pulses.

Clause 65: The system of clause 63 or 64, in which the adjustmentmechanism comprise a wireless receiver in wireless communication with awireless controller.

Clause 66: The system of any of clauses 63-65, wherein the pulsegenerator produces monophasic, rectangular pulses or biphasic pulses.

Clause 67: The system of any of clauses 63-66, wherein the pulsegenerator provides pulses having a pulsewidth of 0.01-3 ms at 1-50 Hz,and wherein the intensity of the pulses is from 2-6 times a toe twitchthreshold of a patient.

Clause 68: The system of any of clauses 63-67, wherein the pulsegenerator provides a fixed output of pulses of 1-100 V and 1-80 mA,having a pulsewidth of 0.01-3 ms, at frequency 1-50 Hz.

Clause 69: A method of treating urological or gastrointestinal disorderscomprising: applying an electrode-containing device of any of clauses51-62 to a foot of a patient in need of such treatment, wherein theelectrode-containing device is attached to a pulse generator external tothe electrode-containing device comprising a connector for connectingthe pulse generator to the device; and stimulating the patient's footwith the device with pulses of between 1-100 V and 1-100 mA, having apulsewidth of 0.01-3 ms, at from 1-50 Hz, thereby stimulating the dorsalintermediate and medial cutaneous nerves, deep peroneal nerve, suralnerve, and/or saphenous nerve of the patient.

Clause 70: The method of clause 69, in which the urological orgastrointestinal disorder is one or more of: overactive bladder (OAB)symptoms including bladder overactivity; urinary frequency; urinaryurgency, urinary incontinence; interstitial cystitis (IC), urinaryretention; pelvic pain; fecal incontinence; irritable bowel syndrome(IBS); and constipation.

Clause 71: The method of clause 69 or 70, wherein the pulse generatorprovides pulses having a pulsewidth of 0.01-3 ms at 1-50 Hz, and whereinthe intensity of the pulses is from 2-6 times a toe twitch threshold ofa patient.

Clause 72: The method of any of clauses 69-71, wherein the patient'sfoot is stimulated for from 1 to 360 minutes.

Clause 73: The method of any of clauses 69-72, wherein the patient'sfoot is stimulated for at least 30 minutes.

Clause 74: The method of any of clauses 69-73, wherein the patient'sfoot is stimulated for at least 90 minutes.

Clause 75: The method of any of clauses 69-74, further comprisingadministering an anti-muscarinic compound to the patient.

Clause 76: The method of clause 75, wherein the anti-muscarinic compoundis selected from the group consisting of atropine, benztropine,biperiden, ipratropium, oxitropium, tiotropium, glycopyrrolate,oxybutynin, tolterodine, chlorpheniramine, diphenhydramine,dimenhydrinate, orphenadrine, trihexyphenidyl, and dicyclomine.

Clause 77: The method of clause 75 or 76, wherein the anti-muscariniccompound is tolterodine.

Clause 78: The method of any of clauses 75-77, wherein theanti-muscarinic compound is administered at between 0.003 and 1 mg/kg.

Clause 79: The method of any of clauses 75-78, wherein theanti-muscarinic compound is administered orally or parenterally.

Clause 80: The method of any of clauses 69-79, further comprisingadministering to a patient in need thereof a serotonin reuptakeinhibitor and/or a serotonin receptor antagonist.

Clause 81: The method of clause 80, wherein the serotonin reuptakeinhibitor is selected from the group consisting of alaproclate,citalopram, dapoxetine, escitalopram, femoxetine, fluoxetine,fluvoxamine, ifoxetine, indalpine, omiloxetine, panuramine, paroxetine,pirandamine, duloxetine, dapoxetine, sertraline, and zimelidine and theserotonin receptor antagonist is selected from the group consisting ofalprenolol, AV-965, BMY-7,378, cyanopindolol, dotarizine, flopropione,GR-46,611, isodocyanopindolol, isamoltane, lecozotan, methiothepin,methysergide, MPPF, NAN-190, oxprenolol, pindobind, pindolol,propranolol, risperidone, robalzotan, SB-649,915 (which acts as both areuptake inhibitor and a receptor antagonist), SDZ-216,525, spiperone,spiramide, spiroxatrine, UH-301, WAY100135, WAY 100635, and xylamidine.

Clause 82: The method of clause 80 or 81, wherein the serotonin reuptakeinhibitor is duloxetine.

Clause 83: The method of any of clauses 80-82, wherein the serotoninreceptor antagonist is WAY100635.

Clause 84: The method of any of clauses 80-83, comprising administeringboth a serotonin reuptake inhibitor and a serotonin receptor antagonist.

Clause 85: The method of any of clauses 80-84, in which the serotoninreuptake inhibitor is duloxetine and the serotonin receptor antagonistis WAY100635.

Clause 86: The method of any of clauses 80-85, wherein the serotoninreuptake inhibitor is administered at between 0.003 and 5 mg/kg and theserotonin receptor antagonist is administered at between 0.1 and 1mg/kg.

Clause 87: The method of any of clauses 80-86, wherein the serotoninreuptake inhibitor or the serotonin receptor antagonist are administeredorally of parenterally.

Clause 88: The method of any of clauses 69-87, further comprisingadministering an opioid drug to the patient.

Clause 89: The method of clause 88, wherein the opioid drug is selectedfrom the group consisting of morphine, codeine, thebaine,diacetylmorphine (morphine diacetate; heroin), nicomorphine (morphinedinicotinate), dipropanoylmorphine (morphine dipropionate),desomorphine, acetylpropionylmorphine, dibenzoylmorphine,diacetyldihydromorphine, hydromorphone, hydrocodone, oxycodone,oxymorphone, ethylmorphine, buprenorphine, fentanyl, pethidine,levorphanol, methadone, tramadol, dextropropoxyphene, tapentadol,endorphins, enkephalins, dynorphins, and endomorphins.

Clause 90: The method of clause 88 or 89, wherein the opioid drug istramadol.

Clause 91: The method of any of clauses 88-90 wherein the opioid drug isadministered at between 0.003 and 1 mg/kg.

Clause 92: The method of any of clauses 88-91, wherein the opioid drugis administered orally or parenterally.

Clause 93: A method of manufacturing an electrode-containing devicecomprising:forming a base adapted to cover a portion of a dorsal surfaceof a human foot including a portion of the forefoot overlaying aplurality of branches of the dorsal intermediate and medial cutaneousnerves, deep peroneal nerve, sural nerve, and/or saphenous nerve, and aportion of the hindfoot overlaying the superficial peroneal nerve, deepperoneal nerve, and/or saphenous nerve; attaching a first electrode tothe base at a position in the base adapted to contact skin overlayingthe superficial peroneal nerve, deep peroneal nerve, and/or saphenousnerve; attaching a second electrode to the base at a position in thebase adapted to contact skin overlaying a plurality of branches of thedorsal intermediate and medial cutaneous nerves, deep peroneal nerve,sural nerve, and/or saphenous nerve in the forefoot; and attachingelectrode leads for the first and second electrodes to the base.

Clause 94: The method of clause 93, wherein the second electrode isadapted to engage skin of the dorsal surface of the foot over at least50% of the width of the forefoot.

Clause 95: The method of clause 93 or 94, in which a plurality of thedevices are manufactured to accommodate a plurality of standardized footsizes.

Clause 96: The method of any of clauses 93-95, in which the electrodesare embedded within the base.

Clause 97: The method of any of clauses 93-96, in which the base isconfigured to have a perimeter having the shape of the dorsal area of afoot from the proximal phalanges to the talocrural joint.

Clause 98: The method of any of clauses 93-97, wherein electrode leadsare embedded within the base.

Clause 99: Use of an electrode-containing device comprising a baseadapted to cover a portion of a dorsal surface of a human foot includinga portion of the forefoot overlaying a plurality of branches of thedorsal intermediate and medial cutaneous nerves, deep peroneal nerve,sural nerve, anchor saphenous nerve, and a portion of the hindfootoverlaying the superficial peroneal nerve, deep peroneal nerve, and/orsaphenous nerve; a first electrode attached to the base at a positionadapted to a dorsal portion of the hindfoot to contact skin overlayingthe superficial peroneal nerve, deep peroneal nerve, and/or saphenousnerve; a second electrode attached to the base at a position adapted toa dorsal portion of the forefoot to contact skin overlaying a pluralityof branches of the dorsal intermediate and medial cutaneous nerves, deepperoneal nerve, sural nerve, and/or saphenous nerve in the forefoot; anda first and second electrical lead attached to the first and secondelectrodes, respectively, for treatment of urinary incontinence,comprising: applying the electrode-containing device to a dorsal surfaceof a foot of a patient in need of such treatment, wherein theelectrode-containing device is attached to a pulse generator external tothe electrode-containing device comprising a connector for connectingthe pulse generator to the device; and stimulating the patient's footwith the device with pulses of between 1-100 V, preferably about 60 V,and 1-100 mA, having a pulsewidth of 0.01-3 ms, at from 1-50 Hz,preferably about 5 Hz, thereby stimulating the dorsal intermediate andmedial cutaneous nerves, deep peroneal nerve, sural nerve, and/orsaphenous nerve of the patient.

Clause 100: Use of an electrode-containing device comprising: a baseadapted to cover a portion of a plantar surface of a human footincluding a portion of the forefoot overlaying a plurality of branchesof the medial or lateral plantar nerves and a portion of the hindfootoverlaying the medial and lateral plantar nerves; a first electrodeattached to the base at a position adapted to the hindfoot to contactskin overlaying the medial and lateral plantar nerves; a secondelectrode attached to the base at a position adapted to the forefoot tocontact skin overlaying a plurality of branches of the medial or lateralplantar nerves in the forefoot; and a first and second electrical leadattached to the first and second electrodes, respectively, for treatmentof urinary incontinence, comprising: applying the electrode-containingdevice to a plantar surface of foot of a patient in need of suchtreatment, wherein the electrode-containing device is attached to apulse generator external to the electrode-containing device comprising aconnector for connecting the pulse generator to the device; andstimulating the patient's foot with the device with pulses of between1-100 V, preferably about 60 V, and 1-100 mA, having a pulsewidth of0.01-3 ms, at from 1-50 Hz, preferably about 5 Hz, thereby stimulatingthe dorsal intermediate and medial cutaneous nerves, deep peronealnerve, sural nerve, and/or saphenous nerve of the patient.

While the present invention has been described in terms of the aboveexamples and detailed description, those of ordinary skill willunderstand that alterations may be made within the spirit of theinvention. Accordingly, the above should not be considered limiting, andthe scope of the invention is defined by the appended claims.

1. An electrode-containing device comprising either: a. a base adapted to cover a portion of a plantar surface of a human foot including a portion of the forefoot overlaying a plurality of branches of the medial or lateral plantar nerves and a portion of the hindfoot overlaying the medial and lateral plantar nerves; a first electrode attached to the base at a position adapted to the hindfoot to contact skin overlaying the medial and lateral plantar nerves; a second electrode attached to the base at a position adapted to the forefoot to contact skin overlaying a plurality of branches of the medial or lateral plantar nerves in the forefoot; and a first and second electrical lead attached to the first and second electrodes, respectively, or b. a base adapted to cover a portion of a dorsal surface of a human foot including a portion of the forefoot overlaying a plurality of branches of the dorsal intermediate and medial cutaneous nerves, deep peroneal nerve, sural nerve, and/or saphenous nerve, and a portion of the hindfoot overlaying the superficial peroneal nerve, deep peroneal nerve, and/or saphenous nerve; a first electrode attached to the base at a position adapted to a dorsal portion of the hindfoot to contact skin overlaying the superficial peroneal nerve, deep peroneal nerve, and/or saphenous nerve; a second electrode attached to the base at a position adapted to a dorsal portion of the forefoot to contact skin overlaying a plurality of branches of the dorsal intermediate and medial cutaneous nerves, deep peroneal nerve, sural nerve, and/or saphenous nerve in the forefoot; and a first and second electrical lead attached to the first and second electrodes, respectively.
 2. The electrode-containing device of claim 1, in which the first electrode is a cathode and the second electrode is an anode, or wherein the first electrode is an anode and the second electrode is a cathode.
 3. The electrode-containing device of claim 2, in which the first electrode or the second electrode overlays at least 50% of the width of the sole at the forefoot.
 4. The electrode-containing device of claim 2, in which the first electrode or the second electrode overlays at least a portion of the metatarsophalangeal joint.
 5. The electrode-containing device of claim 2, in which the first electrode or the second electrode overlays at least a portion of the calcaneus bone.
 6. The electrode-containing device of claim 2, in which the first electrode or the second electrode overlays a predominance of branches of the medial and lateral plantar nerves in the forefoot.
 7. The electrode-containing device of claim 1, wherein the base has a perimeter having the shape of a sole of a foot, and optionally is an orthotic insert, or wherein the base has a perimeter having the shape of the dorsal area of a foot from the proximal phalanges to the talocrural joint.
 8. The electrode-containing device of claim 1, wherein the base is a thin polymeric film having an adhesive on a side comprising the electrodes and facing the foot.
 9. The electrode-containing device of claim 1, further comprising one or more connectors for an external pulse generator attached to the leads.
 10. The electrode-containing device of claim 1, further comprising an adhesive on a surface of the base and/or electrodes for removably securing the device to a patient's foot.
 11. The electrode-containing device of claim 1, wherein the base is shaped substantially like a plantar surface or sole of a human foot, or wherein the base is shaped substantially to interact with the dorsal surface of a human foot.
 12. An electrical nerve stimulation system comprising: an electrode-containing device as claimed in claim 1; a fixed output pulse generator external to the electrode-containing device and connected to the leads, configured to generate monophasic, rectangular, or biphasic pulses of pulsewidth 0.01-3 ms between 1-100 V and 1-80 mA, at frequency 1-50 Hz.
 13. (canceled)
 14. (canceled)
 15. The system of claim 12, wherein the pulse generator provides pulses having a pulsewidth of 0.2 ms at 5 Hz, and wherein the intensity of the pulses is from 2-6 times a toe twitch threshold of a patient.
 16. (canceled)
 17. A method of treating urological or gastrointestinal disorders comprising: applying an electrode-containing device as claimed in claim 1 to a foot of a patient in need of such treatment, wherein the electrode-containing device is attached to a pulse generator external to the electrode-containing device comprising a connector for connecting the pulse generator to the device; stimulating the patient's foot with the device with pulses of pulsewidth 0.01-3 ms between 1-100 V and 1-100 mA, at frequency 1-50 Hz, thereby stimulating either the lateral and/or medial plantar nerves or the dorsal intermediate and medial cutaneous nerves, deep peroneal nerve, sural nerve, and/or saphenous nerves of the patient; and optionally administering to the patient one or more of: an anti-muscarinic compound; a serotonin reuptake inhibitor; a serotonin receptor antagonist; and an opioid drug.
 18. The method of claim 17, in which the urological or gastrointestinal disorder is one or more of: overactive bladder (OAB) symptoms including bladder overactivity, urinary frequency, urinary urgency, urinary incontinence; interstitial cystitis (IC); urinary retention; pelvic pain; fecal incontinence; irritable bowel syndrome (IBS); and constipation.
 19. (canceled)
 20. The method of claim 18, in which the urinary incontinence is bedwetting, and wherein the device delivers pulses of a frequency of 5 Hz, 0.2 ms pulsewidth, and wherein the intensity of the pulse is from 2-6 times a toe twitch threshold of a patient.
 21. The method of claim 17, wherein the patient's foot is stimulated for from 1 to 360 minutes.
 22. (canceled)
 23. (canceled)
 24. The method of claim 17, further comprising administering an anti-muscarinic compound to the patient, wherein the anti-muscarinic compound is selected from the group consisting of atropine, benztropine, biperiden, ipratropium, oxitropium, tiotropium, glycopyrrolate, oxybutynin, tolterodine, chlorpheniramine, diphenhydramine, dimenhydrinate, orphenadrine, trihexyphenidyl, and dicyclomine.
 25. (canceled)
 26. (canceled)
 27. (canceled)
 28. The method of claim 17, further comprising administering to a patient in need thereof a serotonin reuptake inhibitor and/or a serotonin receptor antagonist, wherein the serotonin reuptake inhibitor is selected from the group consisting of alaproclate, citalopram, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, omiloxetine, panuramine, paroxetine, pirandamine, duloxetine, dapoxetine, sertraline, and zimelidine and the serotonin receptor antagonist is selected from the group consisting of alprenolol, AV-965, BMY-7,378, cyanopindolol, dotarizine, flopropione, GR-46,611, isodocyanopindolol, isamoltane, lecozotan, methiothepin, methysergide, MPPF, NAN-190, oxprenolol, pindobind, pindolol, propranolol, risperidone, robalzotan, SB-649,915 (which acts as both a reuptake inhibitor and a receptor antagonist), SDZ-216,525, spiperone, spiramide, spiroxatrine, UH-301, WAY100135, WAY 100635, and xylamidine.
 29. (canceled)
 30. (canceled)
 31. (canceled)
 32. The method of claim 28, comprising administering both a serotonin reuptake inhibitor and a serotonin receptor antagonist, and wherein the serotonin reuptake inhibitor is duloxetine and the serotonin receptor antagonist is WAY100635 and wherein duloxetine is administered at between 0.003 and 5 mg/kg and WAY100635 is administered at between 0.1 and 1 mg/kg.
 33. (canceled)
 34. The method of claim 17, further comprising administering an opioid drug to the patient, wherein the opioid drug is selected from the group consisting of tramadol, morphine, codeine, thebaine, diacetylmorphine (morphine diacetate; heroin), nicomorphine (morphine dinicotinate), dipropanoylmorphine (morphine dipropionate), desomorphine, acetylpropionylmorphine, dibenzoylmorphine, diacetyldihydromorphine, hydromorphone, hydrocodone, oxycodone, oxymorphone, ethylmorphine, buprenorphine, fentanyl, pethidine, levorphanol, methadone, dextropropoxyphene, tapentadol, endorphins, enkephalins, dynorphins, and endomorphins. 35.-43. (canceled) 